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Parchwani D, Singh R, Patel D. Biological and translational attributes of mitochondrial DNA copy number: Laboratory perspective to clinical relevance. World J Methodol 2025; 15:102709. [DOI: 10.5662/wjm.v15.i3.102709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2024] [Revised: 01/21/2025] [Accepted: 02/08/2025] [Indexed: 03/06/2025] Open
Abstract
The mitochondrial DNA copy number (mtDNAcn) plays a vital role in cellular energy metabolism and mitochondrial health. As mitochondria are responsible for adenosine triphosphate production through oxidative phosphorylation, maintaining an appropriate mtDNAcn level is vital for the overall cellular function. Alterations in mtDNAcn have been linked to various diseases, including neurodegenerative disorders, metabolic conditions, and cancers, making it an important biomarker for understanding the disease pathogenesis. The accurate estimation of mtDNAcn is essential for clinical applications. Quantitative polymerase chain reaction and next-generation sequencing are commonly employed techniques with distinct advantages and limitations. Clinically, mtDNAcn serves as a valuable indicator for early diagnosis, disease progression, and treatment response. For instance, in oncology, elevated mtDNAcn levels in blood samples are associated with tumor aggressiveness and can aid in monitoring treatment efficacy. In neurodegenerative diseases such as Alzheimer’s and Parkinson’s, altered mtDNAcn patterns provide insights into disease mechanisms and progression. Understanding and estimating mtDNAcn are critical for advancing diagnostic and therapeutic strategies in various medical fields. As research continues to uncover the implications of mtDNAcn alterations, its potential as a clinical biomarker is likely to expand, thereby enhancing our ability to diagnose and manage complex diseases.
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Affiliation(s)
- Deepak Parchwani
- Department of Biochemistry, All India Institute of Medical Sciences, Rajkot 360001, India
| | - Ragini Singh
- Department of Biochemistry, All India Institute of Medical Sciences, Rajkot 360001, India
| | - Digisha Patel
- Department of Physiology, Shantabaa Medical College and General Hospital Amreli, Amreli 365601, Gujarāt, India
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2
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Men J, Wang X, Zhou Y, Huang Y, Zheng Y, Wang Y, Yang S, Chen N, Yan N, Duan X. Neurodegenerative diseases: Epigenetic regulatory mechanisms and therapeutic potential. Cell Signal 2025; 131:111715. [PMID: 40089090 DOI: 10.1016/j.cellsig.2025.111715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 02/17/2025] [Accepted: 03/03/2025] [Indexed: 03/17/2025]
Abstract
Neurodegenerative diseases (NDDs) are a class of diseases in which the progressive loss of subtype-specific neurons leads to dysfunction. NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), among others. Previous studies have demonstrated that the pathogenesis of NDDs involves various mechanisms, including genetic factors, oxidative stress, apoptosis, and the immune response. Recent studies have shown that epigenetic regulation mediates the interactions between DNA methylation, chromatin remodeling, histone modification, and non-coding RNAs, thus affecting gene transcription. A growing body of research links epigenetic modifications to crucial pathways involved in the occurrence and development of NDDs. Epigenetics has also been found to regulate and maintain nervous system function, and its imbalance is closely related to the occurrence and development of NDDs. The present review summarizes focuses on the role of epigenetic modifications in the pathogenesis of NDDs and provides an overview of the key genes regulated by DNA methylation, histone modification, and non-coding RNAs in NDDs. Further, the current research status of epigenetics in NDDs is summarized and the potential application of epigenetics in the clinical diagnosis and treatment of NDDs is discussed.
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Affiliation(s)
- Jianbing Men
- Department of Toxicology, School of Public Health, Shenyang Medical College, Shenyang 110034, PR China
| | - Xinyue Wang
- Department of Toxicology, School of Public Health, Shenyang Medical College, Shenyang 110034, PR China
| | - Yunnuo Zhou
- Department of Toxicology, School of Public Health, Shenyang Medical College, Shenyang 110034, PR China
| | - Yumeng Huang
- Department of Toxicology, School of Public Health, Shenyang Medical College, Shenyang 110034, PR China
| | - Yue Zheng
- Department of Toxicology, School of Public Health, Shenyang Medical College, Shenyang 110034, PR China
| | - Yingze Wang
- Department of Toxicology, School of Public Health, Shenyang Medical College, Shenyang 110034, PR China
| | - Shuang Yang
- Department of Toxicology, School of Public Health, Shenyang Medical College, Shenyang 110034, PR China
| | - Nan Chen
- Liaoning Provincial Health Service Center,Shenyang 110034, PR China
| | - Nan Yan
- Department of Medical Applied Technology, Shenyang Medical College, Shenyang 110034, PR China.
| | - Xiaoxu Duan
- Department of Toxicology, School of Public Health, Shenyang Medical College, Shenyang 110034, PR China.
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3
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Gao XD, Ding JE, Xie JX, Xu HM. Epigenetic regulation of iron metabolism and ferroptosis in Parkinson's disease: Identifying novel epigenetic targets. Acta Pharmacol Sin 2025:10.1038/s41401-025-01499-6. [PMID: 40069488 DOI: 10.1038/s41401-025-01499-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 01/28/2025] [Indexed: 03/17/2025]
Abstract
Parkinson's disease (PD) is a neurodegenerative disease, and emerging evidence has shown that iron deposition, ferroptosis and epigenetic modifications are implicated in the pathogenesis of PD. However, the interplay among these factors in PD has not been fully understood. In this review, we provide an overview of the current research progress on iron metabolism, ferroptosis and epigenetic alterations associated with PD. Furthermore, we present new frontiers concerning various epigenetic modifications related to iron metabolism and ferroptosis that might contribute to the pathology of PD. Notably, epigenetic modifications of iron metabolism and ferroptosis as both diagnostic and therapeutic targets in PD have been discussed. This opens new avenues for the regulation of iron homeostasis and ferroptosis in PD from epigenetic perspectives, and provides evidence for their potential implications in the diagnosis and treatment of PD.
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Affiliation(s)
- Xiao-Die Gao
- Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Brain Diseases and State Key Disciplines: Physiology, Department of Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Jian-E Ding
- Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Brain Diseases and State Key Disciplines: Physiology, Department of Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Jun-Xia Xie
- Institute of Brain Science and Disease, Qingdao University, Qingdao, 266071, China.
| | - Hua-Min Xu
- Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Brain Diseases and State Key Disciplines: Physiology, Department of Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China.
- Institute of Brain Science and Disease, Qingdao University, Qingdao, 266071, China.
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4
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Liu H, Wang S, Wang J, Guo X, Song Y, Fu K, Gao Z, Liu D, He W, Yang LL. Energy metabolism in health and diseases. Signal Transduct Target Ther 2025; 10:69. [PMID: 39966374 PMCID: PMC11836267 DOI: 10.1038/s41392-025-02141-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 11/08/2024] [Accepted: 12/25/2024] [Indexed: 02/20/2025] Open
Abstract
Energy metabolism is indispensable for sustaining physiological functions in living organisms and assumes a pivotal role across physiological and pathological conditions. This review provides an extensive overview of advancements in energy metabolism research, elucidating critical pathways such as glycolysis, oxidative phosphorylation, fatty acid metabolism, and amino acid metabolism, along with their intricate regulatory mechanisms. The homeostatic balance of these processes is crucial; however, in pathological states such as neurodegenerative diseases, autoimmune disorders, and cancer, extensive metabolic reprogramming occurs, resulting in impaired glucose metabolism and mitochondrial dysfunction, which accelerate disease progression. Recent investigations into key regulatory pathways, including mechanistic target of rapamycin, sirtuins, and adenosine monophosphate-activated protein kinase, have considerably deepened our understanding of metabolic dysregulation and opened new avenues for therapeutic innovation. Emerging technologies, such as fluorescent probes, nano-biomaterials, and metabolomic analyses, promise substantial improvements in diagnostic precision. This review critically examines recent advancements and ongoing challenges in metabolism research, emphasizing its potential for precision diagnostics and personalized therapeutic interventions. Future studies should prioritize unraveling the regulatory mechanisms of energy metabolism and the dynamics of intercellular energy interactions. Integrating cutting-edge gene-editing technologies and multi-omics approaches, the development of multi-target pharmaceuticals in synergy with existing therapies such as immunotherapy and dietary interventions could enhance therapeutic efficacy. Personalized metabolic analysis is indispensable for crafting tailored treatment protocols, ultimately providing more accurate medical solutions for patients. This review aims to deepen the understanding and improve the application of energy metabolism to drive innovative diagnostic and therapeutic strategies.
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Affiliation(s)
- Hui Liu
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shuo Wang
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jianhua Wang
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xin Guo
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yujing Song
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Kun Fu
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhenjie Gao
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Danfeng Liu
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Wei He
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Lei-Lei Yang
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
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5
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Singh P, Paramanik V. DNA methylation, histone acetylation in the regulation of memory and its modulation during aging. FRONTIERS IN AGING 2025; 5:1480932. [PMID: 39835300 PMCID: PMC11743476 DOI: 10.3389/fragi.2024.1480932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 11/27/2024] [Indexed: 01/22/2025]
Abstract
Memory formation is associated with constant modifications of neuronal networks and synaptic plasticity gene expression in response to different environmental stimuli and experiences. Dysregulation of synaptic plasticity gene expression affects memory during aging and neurodegenerative diseases. Covalent modifications such as methylation on DNA and acetylation on histones regulate the transcription of synaptic plasticity genes. Changes in these epigenetic marks correlated with alteration of synaptic plasticity gene expression and memory formation during aging. These epigenetic modifications, in turn, are regulated by physiology and metabolism. Steroid hormone estrogen and metabolites such as S-adenosyl methionine and acetyl CoA directly impact DNA and histones' methylation and acetylation levels. Thus, the decline of estrogen levels or imbalance of these metabolites affects gene expression and underlying brain functions. In the present review, we discussed the importance of DNA methylation and histone acetylation on chromatin modifications, regulation of synaptic plasticity gene expression and memory consolidation, and modulation of these epigenetic marks by epigenetic modifiers such as phytochemicals and vitamins. Further, understanding the molecular mechanisms that modulate these epigenetic modifications will help develop recovery approaches.
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Affiliation(s)
| | - Vijay Paramanik
- Cellular and Molecular Neurobiology & Drug Targeting Laboratory, Department of Zoology, Indira Gandhi National Tribal University, Amarkantak, Madhya Pradesh, India
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Eleuteri S, Wang B, Cutillo G, Zhang Fang TS, Tao K, Qu Y, Yang Q, Wei W, Simon DK. PGC-1α regulation by FBXW7 through a novel mechanism linking chaperone-mediated autophagy and the ubiquitin-proteasome system. FEBS J 2025; 292:332-354. [PMID: 39429232 DOI: 10.1111/febs.17276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 02/21/2024] [Accepted: 09/06/2024] [Indexed: 10/22/2024]
Abstract
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a key regulator of mitochondrial biogenesis and antioxidative defenses, and it may play a critical role in Parkinson's disease (PD). F-box/WD repeat domain-containing protein (FBXW7), an E3 protein ligase, promotes the degradation of substrate proteins through the ubiquitin-proteasome system (UPS) and leads to the clearance of PGC-1α. Here, we elucidate a novel post-translational mechanism for regulating PGC-1α levels in neurons. We show that enhancing chaperone-mediated autophagy (CMA) activity promotes the CMA-mediated degradation of FBXW7 and consequently increases PGC-1α. We confirm the relevance of this pathway in vivo by showing decreased FBXW7 and increased PGC-1α as a result of boosting CMA selectively in dopaminergic (DA) neurons by overexpressing lysosomal-associated membrane protein 2A (LAMP2A) in TH-Cre-LAMP2-loxp conditional mice. We further demonstrate that these mice are protected against MPTP-induced oxidative stress and neurodegeneration. These results highlight a novel regulatory pathway for PGC-1α in DA neurons and suggest targeted increasing of CMA or decreasing FBXW7 in DA neurons as potential neuroprotective strategies in PD.
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Affiliation(s)
- Simona Eleuteri
- Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Bao Wang
- Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Department of Neurosurgery, Tangdu Hospital: Fourth Military Medical University, Xi'an, China
| | - Gianni Cutillo
- Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Tracy Shi Zhang Fang
- Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Kai Tao
- Department of Neurosurgery, Tangdu Hospital: Fourth Military Medical University, Xi'an, China
| | - Yan Qu
- Department of Neurosurgery, Tangdu Hospital: Fourth Military Medical University, Xi'an, China
| | - Qian Yang
- Department of Neurosurgery, Tangdu Hospital: Fourth Military Medical University, Xi'an, China
| | - Wenyi Wei
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - David K Simon
- Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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7
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González Molina LA, Dolga AM, Rots MG, Sarno F. The Promise of Epigenetic Editing for Treating Brain Disorders. Subcell Biochem 2025; 108:111-190. [PMID: 39820862 DOI: 10.1007/978-3-031-75980-2_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2025]
Abstract
Brain disorders, especially neurodegenerative diseases, affect millions of people worldwide. There is no causal treatment available; therefore, there is an unmet clinical need for finding therapeutic options for these diseases. Epigenetic research has resulted in identification of various genomic loci with differential disease-specific epigenetic modifications, mainly DNA methylation. These biomarkers, although not yet translated into clinically approved options, offer therapeutic targets as epigenetic modifications are reversible. Indeed, clinical trials are designed to inhibit epigenetic writers, erasers, or readers using epigenetic drugs to interfere with epigenetic dysregulation in brain disorders. However, since such drugs elicit genome-wide effects and potentially cause toxicity, the recent developments in the field of epigenetic editing are gaining widespread attention. In this review, we provide examples of epigenetic biomarkers and epi-drugs, while describing efforts in the field of epigenetic editing, to eventually make a difference for the currently incurable brain disorders.
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Affiliation(s)
- Luis A González Molina
- Epigenetic Editing, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Molecular Pharmacology, Faculty of Science and Engineering, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Amalia M Dolga
- Department of Molecular Pharmacology, Faculty of Science and Engineering, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Marianne G Rots
- Epigenetic Editing, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Federica Sarno
- Epigenetic Editing, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
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8
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Sharma R, Bisht P, Kesharwani A, Murti K, Kumar N. Epigenetic modifications in Parkinson's disease: A critical review. Eur J Pharmacol 2024; 975:176641. [PMID: 38754537 DOI: 10.1016/j.ejphar.2024.176641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 05/13/2024] [Accepted: 05/13/2024] [Indexed: 05/18/2024]
Abstract
Parkinson's Disease (PD) is a progressive neurodegenerative disorder expected to increase by over 50% by 2030 due to increasing life expectancy. The disease's hallmarks include slow movement, tremors, and postural instability. Impaired protein processing is a major factor in the pathophysiology of PD, leading to the buildup of aberrant protein aggregates, particularly misfolded α-synuclein, also known as Lewy bodies. These Lewy bodies lead to inflammation and further death of dopaminergic neurons, leading to imbalances in excitatory and inhibitory neurotransmitters, causing excessive uncontrollable movements called dyskinesias. It was previously suggested that a complex interplay involving hereditary and environmental variables causes the specific death of neurons in PD; however, the exact mechanism of the association involving the two primary modifiers is yet unknown. An increasing amount of research points to the involvement of epigenetics in the onset and course of several neurological conditions, such as PD. DNA methylation, post-modifications of histones, and non-coding RNAs are the primary examples of epigenetic alterations, that is defined as alterations to the expression of genes and functioning without modifications in DNA sequence. Epigenetic modifications play a significant role in the development of PD, with genes such as Parkin, PTEN-induced kinase 1 (PINK1), DJ1, Leucine-Rich Repeat Kinase 2 (LRRK2), and alpha-synuclein associated with the disease. The aberrant epigenetic changes implicated in the pathophysiology of PD and their impact on the design of novel therapeutic approaches are the primary focus of this review.
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Affiliation(s)
- Ravikant Sharma
- Research Unit of Biomedicine and Internal Medicine, Faculty of Medicine, University of Oulu, Aapistie 5, 90220, Oulu, Finland
| | - Priya Bisht
- Department of Pharmacology and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India
| | - Anuradha Kesharwani
- Department of Pharmacology and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India
| | - Krishna Murti
- Department of Pharmacy Practice, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India
| | - Nitesh Kumar
- Department of Pharmacology and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India.
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Klokkaris A, Migdalska-Richards A. An Overview of Epigenetic Changes in the Parkinson's Disease Brain. Int J Mol Sci 2024; 25:6168. [PMID: 38892355 PMCID: PMC11172855 DOI: 10.3390/ijms25116168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Revised: 05/27/2024] [Accepted: 05/29/2024] [Indexed: 06/21/2024] Open
Abstract
Parkinson's disease is a progressive neurodegenerative disorder, predominantly of the motor system. Although some genetic components and cellular mechanisms of Parkinson's have been identified, much is still unknown. In recent years, emerging evidence has indicated that non-DNA-sequence variation (in particular epigenetic mechanisms) is likely to play a crucial role in the development and progression of the disease. Here, we present an up-to-date overview of epigenetic processes including DNA methylation, DNA hydroxymethylation, histone modifications and non-coding RNAs implicated in the brain of those with Parkinson's disease. We will also discuss the limitations of current epigenetic research in Parkinson's disease, the advantages of simultaneously studying genetics and epigenetics, and putative novel epigenetic therapies.
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Affiliation(s)
| | - Anna Migdalska-Richards
- Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, UK;
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Hassani S, Esmaeili A. The neuroprotective effects of ferulic acid in toxin-induced models of Parkinson's disease: A review. Ageing Res Rev 2024; 97:102299. [PMID: 38604452 DOI: 10.1016/j.arr.2024.102299] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Revised: 03/04/2024] [Accepted: 04/08/2024] [Indexed: 04/13/2024]
Abstract
Parkinson's disease is predominantly caused by dopaminergic neuron loss in the substantia nigra pars compacta and the accumulation of alpha-synuclein protein. Though the general consensus is that several factors, such as aging, environmental factors, mitochondrial dysfunction, accumulations of neurotoxic alpha-synuclein, malfunctions of the lysosomal and proteasomal protein degradation systems, oxidative stress, and neuroinflammation, are involved in the neurodegeneration process of Parkinson's disease, the precise mechanism by which all of these factors are triggered remains unknown. Typically, neurotoxic compounds such as rotenone, 6-hydroxydopamine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-methyl 4-phenyl pyridinium (mpp+), paraquat, and maneb are used to Preclinical models of Parkinson's disease Ferulic acid is often referred to by its scientific name, 4-hydroxy-3-methoxycinnamic acid (C10H10O4), and is found naturally in cereals, fruits, vegetables, and bee products. This substance exhibits neuroprotective effects against Parkinson's disease because of its intriguing potential, which includes anti-inflammatory and antioxidant qualities. This review goes into additional detail about Parkinson's disease and the neuroprotective properties of ferulic acid that may help prevent the condition.
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Affiliation(s)
- Samira Hassani
- Department of Plant and Animal Biology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Abolghasem Esmaeili
- Department of Cell and Molecular Biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.
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Mahmoudian Esfahani M, Mostashfi M, Vaheb Hosseinabadi S, Hashemi MS, Peymani M, Zohrabi D, Angaji SA, Nasr-Esfahani MH, Ghaedi K. Unveiling the regulatory of miR-101-3p on ZNF746 in a Parkinson's disease cell model: Implications for therapeutic targeting. Neurosci Res 2024; 203:18-27. [PMID: 38103579 DOI: 10.1016/j.neures.2023.12.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Revised: 11/08/2023] [Accepted: 12/06/2023] [Indexed: 12/19/2023]
Abstract
In this study, we explored the regulatory role of microRNA miR-101-3p on the zinc finger protein 746 (ZNF746), also known as PARIS, which is implicated in both sporadic and familial forms of Parkinson's disease. In a Parkinson's disease cell model, utilizing SH-SY5Y cells treated with 1-methyl-4-phenylpyridine (MPP+), we observed that miR-101-3p was downregulated, while ZNF746 was upregulated. To investigate the direct impact of miR-101-3p on ZNF746, our team conducted overexpression experiments, successfully reversing ZNF746's expression at both the mRNA and protein levels, as confirmed through quantitative PCR and western blotting. We also performed luciferase assays, providing compelling evidence that ZNF746 is a direct target of miR-101-3p. Additionally, we noted that miR-101-3p overexpression resulted in increased expression of PGC1α, a gene targeted by ZNF746. Functionally, we assessed the implications of miR-101-3p overexpression through MTS assays and flow cytometry, revealing significant promotion of cell viability, inhibition of ROS production, and reduced apoptosis in the Parkinson's disease cell model. In conclusion, this study highlights the role of miR-101-3p in regulating ZNF746 expression and suggests its potential as a therapeutic target for Parkinson's disease. These findings provide valuable molecular insights that could pave the way for innovative treatment strategies in combating this debilitating neurodegenerative disorder.
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Affiliation(s)
| | - Maryam Mostashfi
- Department of Cell and Molecular Biology, Faculty of Biosciences, Kharazmi University, Tehran, Iran
| | | | - Motahare-Sadat Hashemi
- Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Maryam Peymani
- Department of Biology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran.
| | - Dina Zohrabi
- Department of Biology, Faculty of Science, NourDanesh Institute of Higher Education, Isfahan, Iran
| | - Seyed Abdolhamid Angaji
- Department of Cell and Molecular Biology, Faculty of Biosciences, Kharazmi University, Tehran, Iran
| | - Mohammad Hossein Nasr-Esfahani
- Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Kamran Ghaedi
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.
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12
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Prasanth MI, Sivamaruthi BS, Cheong CSY, Verma K, Tencomnao T, Brimson JM, Prasansuklab A. Role of Epigenetic Modulation in Neurodegenerative Diseases: Implications of Phytochemical Interventions. Antioxidants (Basel) 2024; 13:606. [PMID: 38790711 PMCID: PMC11118909 DOI: 10.3390/antiox13050606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 05/10/2024] [Accepted: 05/13/2024] [Indexed: 05/26/2024] Open
Abstract
Epigenetics defines changes in cell function without involving alterations in DNA sequence. Neuroepigenetics bridges neuroscience and epigenetics by regulating gene expression in the nervous system and its impact on brain function. With the increase in research in recent years, it was observed that alterations in the gene expression did not always originate from changes in the genetic sequence, which has led to understanding the role of epigenetics in neurodegenerative diseases (NDDs) including Alzheimer's disease (AD) and Parkinson's disease (PD). Epigenetic alterations contribute to the aberrant expression of genes involved in neuroinflammation, protein aggregation, and neuronal death. Natural phytochemicals have shown promise as potential therapeutic agents against NDDs because of their antioxidant, anti-inflammatory, and neuroprotective effects in cellular and animal models. For instance, resveratrol (grapes), curcumin (turmeric), and epigallocatechin gallate (EGCG; green tea) exhibit neuroprotective effects through their influence on DNA methylation patterns, histone acetylation, and non-coding RNA expression profiles. Phytochemicals also aid in slowing disease progression, preserving neuronal function, and enhancing cognitive and motor abilities. The present review focuses on various epigenetic modifications involved in the pathology of NDDs, including AD and PD, gene expression regulation related to epigenetic alterations, and the role of specific polyphenols in influencing epigenetic modifications in AD and PD.
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Affiliation(s)
- Mani Iyer Prasanth
- Natural Products for Neuroprotection and Anti-Ageing Research Unit, Chulalongkorn University, Bangkok 10330, Thailand; (M.I.P.); (C.S.Y.C.); (K.V.); (T.T.); (J.M.B.)
- Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Bhagavathi Sundaram Sivamaruthi
- Office of Research Administration, Chiang Mai University, Chiang Mai 50200, Thailand;
- Innovation Center for Holistic Health, Nutraceuticals, and Cosmeceuticals, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Clerance Su Yee Cheong
- Natural Products for Neuroprotection and Anti-Ageing Research Unit, Chulalongkorn University, Bangkok 10330, Thailand; (M.I.P.); (C.S.Y.C.); (K.V.); (T.T.); (J.M.B.)
- Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Kanika Verma
- Natural Products for Neuroprotection and Anti-Ageing Research Unit, Chulalongkorn University, Bangkok 10330, Thailand; (M.I.P.); (C.S.Y.C.); (K.V.); (T.T.); (J.M.B.)
- Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Tewin Tencomnao
- Natural Products for Neuroprotection and Anti-Ageing Research Unit, Chulalongkorn University, Bangkok 10330, Thailand; (M.I.P.); (C.S.Y.C.); (K.V.); (T.T.); (J.M.B.)
- Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - James Michael Brimson
- Natural Products for Neuroprotection and Anti-Ageing Research Unit, Chulalongkorn University, Bangkok 10330, Thailand; (M.I.P.); (C.S.Y.C.); (K.V.); (T.T.); (J.M.B.)
- Research, Innovation and International Affairs, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Anchalee Prasansuklab
- Natural Products for Neuroprotection and Anti-Ageing Research Unit, Chulalongkorn University, Bangkok 10330, Thailand; (M.I.P.); (C.S.Y.C.); (K.V.); (T.T.); (J.M.B.)
- College of Public Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand
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13
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Zhang Z, Wang R, Zhou H, Wu D, Cao Y, Zhang C, Sun H, Mu C, Hao Z, Ren H, Wang N, Yu S, Zhang J, Tao M, Wang C, Liu Y, Liu L, Liu Y, Zang J, Wang G. Inhibition of EHMT1/2 rescues synaptic damage and motor impairment in a PD mouse model. Cell Mol Life Sci 2024; 81:128. [PMID: 38472451 DOI: 10.1007/s00018-024-05176-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 01/16/2024] [Accepted: 02/14/2024] [Indexed: 03/14/2024]
Abstract
Epigenetic dysregulation that leads to alterations in gene expression and is suggested to be one of the key pathophysiological factors of Parkinson's disease (PD). Here, we found that α-synuclein preformed fibrils (PFFs) induced histone H3 dimethylation at lysine 9 (H3K9me2) and increased the euchromatic histone methyltransferases EHMT1 and EHMT2, which were accompanied by neuronal synaptic damage, including loss of synapses and diminished expression levels of synaptic-related proteins. Furthermore, the levels of H3K9me2 at promoters in genes that encode the synaptic-related proteins SNAP25, PSD95, Synapsin 1 and vGLUT1 were increased in primary neurons after PFF treatment, which suggests a linkage between H3K9 dimethylation and synaptic dysfunction. Inhibition of EHMT1/2 with the specific inhibitor A-366 or shRNA suppressed histone methylation and alleviated synaptic damage in primary neurons that were treated with PFFs. In addition, the synaptic damage and motor impairment in mice that were injected with PFFs were repressed by treatment with the EHMT1/2 inhibitor A-366. Thus, our findings reveal the role of histone H3 modification by EHMT1/2 in synaptic damage and motor impairment in a PFF animal model, suggesting the involvement of epigenetic dysregulation in PD pathogenesis.
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Affiliation(s)
- Zhixiong Zhang
- Laboratory of Molecular Neuropathology, Department of Pharmacology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Rui Wang
- Laboratory of Molecular Neuropathology, Department of Pharmacology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Hui Zhou
- Laboratory of Molecular Neuropathology, Department of Pharmacology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Dan Wu
- Laboratory of Molecular Neuropathology, Department of Pharmacology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Yifan Cao
- Laboratory of Molecular Neuropathology, Department of Pharmacology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Chuang Zhang
- Laboratory of Molecular Neuropathology, Department of Pharmacology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Hongyang Sun
- Laboratory of Molecular Neuropathology, Department of Pharmacology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Chenchen Mu
- Laboratory of Molecular Neuropathology, Department of Pharmacology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Zongbing Hao
- Laboratory of Molecular Neuropathology, Department of Pharmacology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Haigang Ren
- Laboratory of Molecular Neuropathology, Department of Pharmacology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China
- Jiangsu Provincial Medical Innovation Center of Trauma Medicine, Institute of Trauma Medicine, Soochow University, Suzhou, 215123, Jiangsu, China
- MOE Key Laboratory of Geriatric Diseases and Immunology, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Nana Wang
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, 215163, China
| | - Shuang Yu
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, 215163, China
| | - Jingzhong Zhang
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, 215163, China
| | - Mengdan Tao
- School of Pharmacy, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211166, China
| | - Can Wang
- School of Pharmacy, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211166, China
| | - Yan Liu
- School of Pharmacy, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211166, China
| | - Liu Liu
- Department of Pharmacy, The First Affiliated Hospital of Hunan Normal University, Hunan Provincial People's Hospital, Changsha, 410005, China
| | - Yanli Liu
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Jianye Zang
- Hefei National Laboratory for Physical Sciences at Microscale CAS Center for Excellence in Biomacromolecules, Collaborative Innovation Center of Chemistry for Life Sciences, and School of Life Sciences, University of Science and Technology of China, 96 Jinzhai Road, Hefei, 230026, Anhui, China
| | - Guanghui Wang
- Laboratory of Molecular Neuropathology, Department of Pharmacology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China.
- MOE Key Laboratory of Geriatric Diseases and Immunology, Soochow University, Suzhou, 215123, Jiangsu, China.
- Center of Translational Medicine, First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, Suzhou, 215400, China.
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14
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Rani N, Sahu M, Ambasta RK, Kumar P. Triaging between post-translational modification of cell cycle regulators and their therapeutics in neurodegenerative diseases. Ageing Res Rev 2024; 94:102174. [PMID: 38135008 DOI: 10.1016/j.arr.2023.102174] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 12/18/2023] [Accepted: 12/18/2023] [Indexed: 12/24/2023]
Abstract
Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, present challenges in healthcare because of their complicated etiologies and absence of healing remedies. Lately, the emerging role of post-translational modifications (PTMs), in the context of cell cycle regulators, has garnered big interest as a potential avenue for therapeutic intervention. The review explores the problematic panorama of PTMs on cell cycle regulators and their implications in neurodegenerative diseases. We delve into the dynamic phosphorylation, acetylation, ubiquitination, SUMOylation, Glycation, and Neddylation that modulate the key cell cycle regulators, consisting of cyclins, cyclin-dependent kinases (CDKs), and their inhibitors. The dysregulation of these PTMs is related to aberrant cell cycle in neurons, which is one of the factors involved in neurodegenerative pathologies. Moreover, the effect of exogenous activation of CDKs and CDK inhibitors through PTMs on the signaling cascade was studied in postmitotic conditions of NDDs. Furthermore, the therapeutic implications of CDK inhibitors and associated alteration in PTMs were discussed. Lastly, we explored the putative mechanism of PTMs to restore normal neuronal function that might reverse NDDs.
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Affiliation(s)
- Neetu Rani
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly DCE), Delhi 110042
| | - Mehar Sahu
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly DCE), Delhi 110042
| | - Rashmi K Ambasta
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly DCE), Delhi 110042; Department of Biotechnology and Microbiology, SRM University, Sonepat, Haryana, India.
| | - Pravir Kumar
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly DCE), Delhi 110042.
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15
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Chen YC, Liaw YC, Nfor ON, Hsiao CH, Zhong JH, Wu SL, Liaw YP. Epigenetic regulation of Parkinson's disease risk variant GPNMB cg17274742 methylation by sex and exercise from Taiwan Biobank. Front Aging Neurosci 2023; 15:1235840. [PMID: 37744396 PMCID: PMC10513104 DOI: 10.3389/fnagi.2023.1235840] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 08/23/2023] [Indexed: 09/26/2023] Open
Abstract
Background Parkinson's disease (PD) is a complex neurodegenerative disease with an elusive etiology that involves the interaction between genetic, behavioral, and environmental factors. Recently, epigenetic modifications, particularly DNA methylation, have been recognized to play an important role in the onset of PD. Glycoprotein non-metastatic melanoma protein B (GPNMB), a type I transmembrane protein crucial for immune cell activation and maturation, has emerged as a potential biomarker for the risk of PD. This research aims to investigate the influence of exercise and gender on the regulation of methylation levels of GPNMB cg17274742 in individuals. Methods We analyze data from 2,474 participants in the Taiwan Biobank, collected from 2008 and 2016. Methylation levels at the GPNMB cg17274742 CpG site were measured using Illumina Infinium MethylationEPIC beads. After excluding individuals with incomplete data or missing information on possible risk factors, our final analysis included 1,442 participants. We used multiple linear regression models to assess the association between sex and exercise with adjusted levels of GPNMB cg17274742 for age, BMI, smoking, drinking, coffee consumption, serum uric acid levels, and hypertension. Results Our results demonstrated that exercise significantly influenced the methylation levels of GPNMB cg17274742 in males (β = -0.00242; p = 0.0026), but not in females (β = -0.00002362; p = 0.9785). Furthermore, male participants who exercised showed significantly lower levels of methylation compared to the reference groups of the female and non-exercising reference groups (β = -0.00357; p = 0.0079). The effect of the interaction between gender and exercise on the methylation of GPNMB cg17274742 was statistically significant (p = 0.0078). Conclusion This study suggests that gender and exercise can modulate GPNMB cg17274742, with hypomethylation observed in exercise men. More research is needed to understand the underlying mechanisms and implications of these epigenetic changes in the context of risk and prevention strategies.
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Affiliation(s)
- Yen-Chung Chen
- Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung, Taiwan
- Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan
| | - Yi-Chia Liaw
- Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Oswald Ndi Nfor
- Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung, Taiwan
| | - Chih-Hsuan Hsiao
- Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung, Taiwan
| | - Ji-Han Zhong
- Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung, Taiwan
| | - Shey-Lin Wu
- Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan
- Department of Electrical Engineering, Changhua National University of Education, Changhua, Taiwan
| | - Yung-Po Liaw
- Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung, Taiwan
- Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung, Taiwan
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
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16
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Zhang D, Zhang J, Wang Y, Wang G, Tang P, Liu Y, Zhang Y, Ouyang L. Targeting epigenetic modifications in Parkinson's disease therapy. Med Res Rev 2023; 43:1748-1777. [PMID: 37119043 DOI: 10.1002/med.21962] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 01/10/2023] [Accepted: 04/12/2023] [Indexed: 04/30/2023]
Abstract
Parkinson's disease (PD) is a multifactorial disease due to a complex interplay between genetic and epigenetic factors. Recent efforts shed new light on the epigenetic mechanisms involved in regulating pathways related to the development of PD, including DNA methylation, posttranslational modifications of histones, and the presence of microRNA (miRNA or miR). Epigenetic regulators are potential therapeutic targets for neurodegenerative disorders. In the review, we aim to summarize mechanisms of epigenetic regulation in PD, and describe how the DNA methyltransferases, histone deacetylases, and histone acetyltransferases that mediate the key processes of PD are attractive therapeutic targets. We discuss the use of inhibitors and/or activators of these regulators in PD models or patients, and how these small molecule epigenetic modulators elicit neuroprotective effects. Further more, given the importance of miRNAs in PD, their contributions to the underlying mechanisms of PD will be discussed as well, together with miRNA-based therapies.
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Affiliation(s)
- Dan Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy and Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics，West China Hospital, Sichuan University, Sichuan, Chengdu, China
| | - Jifa Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy and Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics，West China Hospital, Sichuan University, Sichuan, Chengdu, China
| | - Yuxi Wang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy and Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics，West China Hospital, Sichuan University, Sichuan, Chengdu, China
- Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Guan Wang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy and Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics，West China Hospital, Sichuan University, Sichuan, Chengdu, China
| | - Pan Tang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy and Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics，West China Hospital, Sichuan University, Sichuan, Chengdu, China
| | - Yun Liu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy and Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics，West China Hospital, Sichuan University, Sichuan, Chengdu, China
| | - Yiwen Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy and Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics，West China Hospital, Sichuan University, Sichuan, Chengdu, China
| | - Liang Ouyang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy and Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics，West China Hospital, Sichuan University, Sichuan, Chengdu, China
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17
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Lomeli-Lepe AK, Castañeda-Cabral JL, López-Pérez SJ. Synucleinopathies: Intrinsic and Extrinsic Factors. Cell Biochem Biophys 2023; 81:427-442. [PMID: 37526884 DOI: 10.1007/s12013-023-01154-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 07/23/2023] [Indexed: 08/02/2023]
Abstract
α-Synucleinopathies are a group of neurodegenerative disorders characterized by alterations in α-synuclein (α-syn), a protein associated with membrane phospholipids, whose precise function in normal cells is still unknown. These kinds of diseases are caused by multiple factors, but the regulation of the α-syn gene is believed to play a central role in the pathology of these disorders; therefore, the α-syn gene is one of the most studied genes. α-Synucleinopathies are complex disorders that derive from the interaction between genetic and environmental factors. Here, we offer an update on the landscape of the epigenetic regulation of α-syn gene expression that has been linked with α-synucleinopathies. We also delve into the reciprocal influence between epigenetic modifications and other factors related to these disorders, such as posttranslational modifications, microbiota participation, interactions with lipids, neuroinflammation and oxidative stress, to promote α-syn aggregation by acting on the transcription and/or translation of the α-syn gene.
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Affiliation(s)
- Alma Karen Lomeli-Lepe
- Departamento de Biología Celular y Molecular, CUCBA, Universidad de Guadalajara, Guadalajara, JAL, México
| | - Jose Luis Castañeda-Cabral
- Departamento de Biología Celular y Molecular, CUCBA, Universidad de Guadalajara, Guadalajara, JAL, México
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18
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Uppala SN, Tryphena KP, Naren P, Srivastava S, Singh SB, Khatri DK. Involvement of miRNA on Epigenetics landscape of Parkinson's disease: From pathogenesis to therapeutics. Mech Ageing Dev 2023:111826. [PMID: 37268278 DOI: 10.1016/j.mad.2023.111826] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 05/21/2023] [Accepted: 05/29/2023] [Indexed: 06/04/2023]
Abstract
The development of novel therapeutics for the effective management of Parkinson's disease (PD) is undertaken seriously by the scientific community as the burden of PD continues to increase. Several molecular pathways are being explored to identify novel therapeutic targets. Epigenetics is strongly implicated in several neurodegenerative diseases (NDDs) including PD. Several epigenetic mechanisms were found to dysregulated in various studies. These mechanisms are regulated by several miRNAs which are associated with a variety of pathogenic mechanisms in PD. This concept is extensively investigated in several cancers but not well documented in PD. Identifying the miRNAs with dual role i.e., regulation of epigenetic mechanisms as well as modulation of proteins implicated in the pathogenesis of PD could pave way for the development of novel therapeutics to target them. These miRNAs could also serve as potential biomarkers and can be useful in the early diagnosis or assessment of disease severity. In this article we would like to discuss about various epigenetic changes operating in PD and how miRNAs are involved in the regulation of these mechanisms and their potential to be novel therapeutic targets in PD.
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Affiliation(s)
- Sai Nikhil Uppala
- Molecular and cellular neuroscience lab, Department of pharmacology and toxicology, National Institute of Pharmaceutical Education and Research (NIPER)- Hyderabad, Telangana-500037
| | - Kamatham Pushpa Tryphena
- Molecular and cellular neuroscience lab, Department of pharmacology and toxicology, National Institute of Pharmaceutical Education and Research (NIPER)- Hyderabad, Telangana-500037
| | - Padmashri Naren
- Molecular and cellular neuroscience lab, Department of pharmacology and toxicology, National Institute of Pharmaceutical Education and Research (NIPER)- Hyderabad, Telangana-500037
| | - Saurabh Srivastava
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)- Hyderabad, Telangana-500037
| | - Shashi Bala Singh
- Molecular and cellular neuroscience lab, Department of pharmacology and toxicology, National Institute of Pharmaceutical Education and Research (NIPER)- Hyderabad, Telangana-500037.
| | - Dharmendra Kumar Khatri
- Molecular and cellular neuroscience lab, Department of pharmacology and toxicology, National Institute of Pharmaceutical Education and Research (NIPER)- Hyderabad, Telangana-500037.
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19
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Methylation-sensitive transcription-enhanced single-molecule biosensing of DNA methylation in cancer cells and tissues. Anal Chim Acta 2023; 1251:340996. [PMID: 36925287 DOI: 10.1016/j.aca.2023.340996] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Accepted: 02/21/2023] [Indexed: 02/24/2023]
Abstract
As a major epigenetic modification, DNA methylation participates in diverse cellular functions and emerges as a promising biomarker for disease diagnosis and monitoring. Herein, we developed a methylation-sensitive transcription-enhanced single-molecule biosensor to detect DNA methylation in human cells and tissues. In this biosensor, a rationally designed transcription machine is split into two parts including a promoter sequence (probe-P) for initiating transcription and a template sequence (probe-T) for RNA synthesis. The presence of specific DNA methylation leads to the formation of full-length transcription machine through sequence-specific ligation of probe-P and probe-T, initiating the synthesis of abundant ssRNA transcripts. The resultant ssRNAs can activate CRISPR/Cas12a to catalyze cyclic cleavage of fluorophore- and quencher-dual labeled signal probes, resulting in the recovery of the fluorophore signal that can be quantified by single-molecule detection. Taking advantages of the high-fidelity ligation of split transcription machine and the high efficiency of transcription- and CRISPR/Cas12a cleavage-mediated dual signal amplification, this single-molecule biosensor achieves a low detection limit of 337 aM and high selectivity. Moreover, it can distinguish 0.01% methylation level, and even accurately detect genomic DNA methylation in single cell and clinical samples, providing a powerful tool for epigenetic researches and clinical diagnostics.
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20
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Neto IVDS, Pinto AP, Muñoz VR, de Cássia Marqueti R, Pauli JR, Ropelle ER, Silva ASRD. Pleiotropic and multi-systemic actions of physical exercise on PGC-1α signaling during the aging process. Ageing Res Rev 2023; 87:101935. [PMID: 37062444 DOI: 10.1016/j.arr.2023.101935] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 04/10/2023] [Accepted: 04/13/2023] [Indexed: 04/18/2023]
Abstract
Physical training is a potent therapeutic approach for improving mitochondrial health through peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) signaling pathways. However, comprehensive information regarding the physical training impact on PGC-1α in the different physiological systems with advancing age is not fully understood. This review sheds light on the frontier-of-knowledge data regarding the chronic effects of exercise on the PGC-1α signaling pathways in rodents and humans. We address the molecular mechanisms involved in the different tissues, clarifying the precise biological action of PGC-1α, restricted to the aged cell type. Distinct exercise protocols (short and long-term) and modalities (aerobic and resistance exercise) increase the transcriptional and translational PGC-1α levels in adipose tissue, brain, heart, liver, and skeletal muscle in animal models, suggesting that this versatile molecule induces pleiotropic responses. However, PGC-1α function in some human tissues (adipose tissue, heart, and brain) remains challenging for further investigations. PGC-1α is not a simple transcriptional coactivator but supports a biochemical environment of mitochondrial dynamics, controlling physiological processes (primary metabolism, tissue remodeling, autophagy, inflammation, and redox balance). Acting as an adaptive mechanism, the long-term effects of PGC-1α following exercise may reflect the energy demand to coordinate multiple organs and contribute to cellular longevity.
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Affiliation(s)
- Ivo Vieira de Sousa Neto
- School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil.
| | - Ana Paula Pinto
- School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
| | - Vitor Rosetto Muñoz
- School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
| | - Rita de Cássia Marqueti
- Molecular Analysis Laboratory, Faculty of Ceilândia, Universidade de Brasília (UNB), Distrito Federal, Brazil
| | - José Rodrigo Pauli
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeira, São Paulo 13484-350, Brazil
| | - Eduardo Rochete Ropelle
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeira, São Paulo 13484-350, Brazil
| | - Adelino Sanchez Ramos da Silva
- School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil.
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21
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Jia J, Qin L, Lei R. DGA-5mC: A 5-methylcytosine site prediction model based on an improved DenseNet and bidirectional GRU method. MATHEMATICAL BIOSCIENCES AND ENGINEERING : MBE 2023; 20:9759-9780. [PMID: 37322910 DOI: 10.3934/mbe.2023428] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
The 5-methylcytosine (5mC) in the promoter region plays a significant role in biological processes and diseases. A few high-throughput sequencing technologies and traditional machine learning algorithms are often used by researchers to detect 5mC modification sites. However, high-throughput identification is laborious, time-consuming and expensive; moreover, the machine learning algorithms are not so advanced. Therefore, there is an urgent need to develop a more efficient computational approach to replace those traditional methods. Since deep learning algorithms are more popular and have powerful computational advantages, we constructed a novel prediction model, called DGA-5mC, to identify 5mC modification sites in promoter regions by using a deep learning algorithm based on an improved densely connected convolutional network (DenseNet) and the bidirectional GRU approach. Furthermore, we added a self-attention module to evaluate the importance of various 5mC features. The deep learning-based DGA-5mC model algorithm automatically handles large proportions of unbalanced data for both positive and negative samples, highlighting the model's reliability and superiority. So far as the authors are aware, this is the first time that the combination of an improved DenseNet and bidirectional GRU methods has been used to predict the 5mC modification sites in promoter regions. It can be seen that the DGA-5mC model, after using a combination of one-hot coding, nucleotide chemical property coding and nucleotide density coding, performed well in terms of sensitivity, specificity, accuracy, the Matthews correlation coefficient (MCC), area under the curve and Gmean in the independent test dataset: 90.19%, 92.74%, 92.54%, 64.64%, 96.43% and 91.46%, respectively. In addition, all datasets and source codes for the DGA-5mC model are freely accessible at https://github.com/lulukoss/DGA-5mC.
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Affiliation(s)
- Jianhua Jia
- School of Information Engineering, Jingdezhen Ceramic University, Jingdezhen 333403, China
| | - Lulu Qin
- School of Information Engineering, Jingdezhen Ceramic University, Jingdezhen 333403, China
| | - Rufeng Lei
- School of Information Engineering, Jingdezhen Ceramic University, Jingdezhen 333403, China
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22
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Guan X, Wu P, Cao B, Liu X, Chen X, Zhang W, Zhang Y, Guan Z, Wang Y. PGC-1α-siRNA suppresses inflammation in substantia nigra of PD mice by inhibiting microglia. Int J Neurosci 2023; 133:269-277. [PMID: 33784949 DOI: 10.1080/00207454.2021.1910257] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Background and purpose: Parkinson's disease is a common degenerative disease of the central nervous system with complex pathogenesis. More and more studies have found that inflammatory response promotes the occurrence and development of the disease, in which the activation of microglia plays an important role. PGC-1α (peroxisome proliferator activated receptor-γ coactivator-1α) is the main factor in mitochondrial biogenetic, and is closely related to the inflammatory response. Our immunofluorescence test results showed that PGC-1α and microglia (Iba1) have double-labeled phenomenon. The expression of microglia in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) group increased, and PGC-1α/Iba1 double label increased. To test whether lowering the expression of PGC-1α can reduce the activation of microglia and protect the substantia nigra dopaminergic neurons, we constructed PGC-1α interference lentivirus.Methods: Immunofluorescence, western blot, and ELISA were used to detect microglial phenotype.Results: The results showed that PGC-1α interfering with lentivirus can transfect microglial cells in substantia nigra, and the PGC-1α protein level decreased in substantia nigra accordingly; TH protein expression had no statistical difference compared with MPTP group; PGC-1α interfering lentivirus reduced microglia number and activation, and at the same time the expression of iNOS and Arg1 significantly reduced compared with MPTP group. The IL-6 expression in blood detected using ELISA was significantly reduced compared with MPTP group.Conclusion: PGC-1α downregulation inhibited microglia activity, and both M1 and M2 microglial activities are reduced.
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Affiliation(s)
- Xin Guan
- Department of Physiology, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, PR China
| | - Pengyue Wu
- Department of Physiology, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, PR China
| | - Bing Cao
- Department of Physiology, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, PR China
| | - Xiaoting Liu
- Department of Physiology, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, PR China
| | - Xi Chen
- Department of Physiology, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, PR China
| | - Wenpei Zhang
- Department of Physiology, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, PR China
| | - Yanqiu Zhang
- Department of Physiology, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, PR China
| | - Zhenlong Guan
- Department of Physiology, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, PR China
| | - Yanqin Wang
- Department of Physiology, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, PR China
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Yu S, Cao S, He S, Zhang K. Locus-Specific Detection of DNA Methylation: The Advance, Challenge, and Perspective of CRISPR-Cas Assisted Biosensors. SMALL METHODS 2023; 7:e2201624. [PMID: 36609885 DOI: 10.1002/smtd.202201624] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Indexed: 06/17/2023]
Abstract
Deoxyribonucleic acid (DNA) methylation is one of the epigenetic characteristics that result in heritable and revisable phenotype changes but without sequence changes in DNA. Aberrant methylation occurring at a specific locus was reported to be associated with cancers, insulin resistance, obesity, Alzheimer's disease, Parkinson's disease, etc. Therefore, locus-specific DNA methylation can serve as a valuable biomarker for disease diagnosis and therapy. Recently, Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas systems are applied to develop biosensors for DNA, ribonucleic acid, proteins, and small molecules detection. Because of their highly specific binding ability and signal amplification capacity, CRISPR-Cas assisted biosensor also serve as a potential tool for locus-specific detection of DNA methylation. In this perspective, based on the detection principle, a detailed classification and comprehensive discussion of recent works about the latest advances in locus-specific detection of DNA methylation using CRISPR-Cas systems are provided. Furthermore, current challenges and future perspectives of CRISPR-based locus-specific detection of DNA methylation are outlined.
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Affiliation(s)
- Songcheng Yu
- College of Public Health, Zhengzhou University, No.100 Science Avenue, Zhengzhou City, 450001, P. R. China
| | - Shengnan Cao
- College of Public Health, Zhengzhou University, No.100 Science Avenue, Zhengzhou City, 450001, P. R. China
| | - Sitian He
- College of Public Health, Zhengzhou University, No.100 Science Avenue, Zhengzhou City, 450001, P. R. China
| | - Kaixiang Zhang
- School of Pharmaceutical Sciences, Zhengzhou University, No.100 Science Avenue, Zhengzhou City, 450001, P. R. China
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24
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Kulkarni A, Preeti K, Tryphena KP, Srivastava S, Singh SB, Khatri DK. Proteostasis in Parkinson's disease: Recent development and possible implication in diagnosis and therapeutics. Ageing Res Rev 2023; 84:101816. [PMID: 36481490 DOI: 10.1016/j.arr.2022.101816] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 11/27/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022]
Abstract
The protein dyshomeostasis is identified as the hallmark of many age-related neurodegenerative disorders including Parkinson's disease (PD). The diseased brain shows the deposition of Lewy bodies composed of α-synuclein protein aggregates. Functional proteostasis is characterized by the well-coordinated signaling network constituting unfolded protein response (UPR), the ubiquitin-proteasome system (UPS), and the autophagy-lysosome pathway (ALP). These networks ensure proper synthesis, folding, confirmation, and degradation of protein i.e., α-synuclein protein in PD. The proper functioning the of intricately woven proteostasis network is quite resilient to sustain under the influence of stressors. The synuclein protein turnover is hugely influenced by the autosomal dominant, recessive, and X-linked mutational changes of a gene involved in UPR, UPS, and ALP. The methylation, acetylation-related epigenetic modifications of DNA and histone proteins along with microRNA-mediated transcriptional changes also lead to extensive proteostasis dysregulation. The result of defective proteostasis is the deposition of many proteins which start appearing in the biofluids and can be identified as potential biomarkers for early diagnosis of PD. The therapeutic intervention targeted at different strata of proteostasis machinery holds great possibilities for delaying the age-related accumulation of pathological hallmarks.
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Affiliation(s)
- Amrita Kulkarni
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education, and Research (NIPER), Hyderabad, Telangana 500037, India
| | - Kumari Preeti
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education, and Research (NIPER), Hyderabad, Telangana 500037, India
| | - Kamatham Pushpa Tryphena
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education, and Research (NIPER), Hyderabad, Telangana 500037, India
| | - Saurabh Srivastava
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana 500037, India
| | - Shashi Bala Singh
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education, and Research (NIPER), Hyderabad, Telangana 500037, India
| | - Dharmendra Kumar Khatri
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education, and Research (NIPER), Hyderabad, Telangana 500037, India.
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25
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Xie J, Xie L, Wei H, Li XJ, Lin L. Dynamic Regulation of DNA Methylation and Brain Functions. BIOLOGY 2023; 12:152. [PMID: 36829430 PMCID: PMC9952911 DOI: 10.3390/biology12020152] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/10/2023] [Accepted: 01/16/2023] [Indexed: 01/21/2023]
Abstract
DNA cytosine methylation is a principal epigenetic mechanism underlying transcription during development and aging. Growing evidence suggests that DNA methylation plays a critical role in brain function, including neurogenesis, neuronal differentiation, synaptogenesis, learning, and memory. However, the mechanisms underlying aberrant DNA methylation in neurodegenerative diseases remain unclear. In this review, we provide an overview of the contribution of 5-methycytosine (5mC) and 5-hydroxylcytosine (5hmC) to brain development and aging, with a focus on the roles of dynamic 5mC and 5hmC changes in the pathogenesis of neurodegenerative diseases, particularly Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Identification of aberrant DNA methylation sites could provide potential candidates for epigenetic-based diagnostic and therapeutic strategies for neurodegenerative diseases.
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Affiliation(s)
| | | | | | - Xiao-Jiang Li
- Guangdong Key Laboratory of Non-Human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China
| | - Li Lin
- Guangdong Key Laboratory of Non-Human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China
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26
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Yazar V, Dawson VL, Dawson TM, Kang SU. DNA Methylation Signature of Aging: Potential Impact on the Pathogenesis of Parkinson's Disease. JOURNAL OF PARKINSON'S DISEASE 2023; 13:145-164. [PMID: 36710687 PMCID: PMC10041453 DOI: 10.3233/jpd-223517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Regulation of gene expression by epigenetic modifications means lasting and heritable changes in the function of genes without alterations in the DNA sequence. Of all epigenetic mechanisms identified thus far, DNA methylation has been of particular interest in both aging and age-related disease research over the last decade given the consistency of site-specific DNA methylation changes during aging that can predict future health and lifespan. An increasing line of evidence has implied the dynamic nature of DNA (de)methylation events that occur throughout the lifespan has a role in the pathophysiology of aging and age-associated neurodegenerative conditions, including Parkinson's disease (PD). In this regard, PD methylome shows, to some extent, similar genome-wide changes observed in the methylome of healthy individuals of matching age. In this review, we start by providing a brief overview of studies outlining global patterns of DNA methylation, then its mechanisms and regulation, within the context of aging and PD. Considering diverging lines of evidence from different experimental and animal models of neurodegeneration and how they combine to shape our current understanding of tissue-specific changes in DNA methylome in health and disease, we report a high-level comparison of the genomic methylation landscapes of brain, with an emphasis on dopaminergic neurons in PD and in natural aging. We believe this will be particularly useful for systematically dissecting overlapping genome-wide alterations in DNA methylation during PD and healthy aging, and for improving our knowledge of PD-specific changes in methylation patterns independent of aging process.
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Affiliation(s)
- Volkan Yazar
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Valina L Dawson
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA
- Diana Helis Henry Medical Research Foundation, New Orleans, LA, USA
| | - Ted M Dawson
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Pharmacology and and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA
- Diana Helis Henry Medical Research Foundation, New Orleans, LA, USA
| | - Sung-Ung Kang
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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27
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Li D, Liang J, Guo W, Zhang Y, Wu X, Zhang W. Integrative analysis of DNA methylation and gene expression data for the diagnosis and underlying mechanism of Parkinson’s disease. Front Aging Neurosci 2022; 14:971528. [PMID: 36062142 PMCID: PMC9434001 DOI: 10.3389/fnagi.2022.971528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 08/03/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundParkinson’s disease (PD) is the second most common progressive neurodegenerative disorder and the leading cause of disability in the daily activities. In the management of PD, accurate and specific biomarkers in blood for the early diagnosis of PD are urgently needed. DNA methylation is one of the main epigenetic mechanisms and associated with the gene expression and disease initiation of PD. We aimed to construct a methylation signature for the diagnosis of PD patients, and explore the potential value of DNA methylation in therapeutic options.Materials and methodsWhole blood DNA methylation and gene expression data of PD patients as well as healthy controls were extracted from Gene Expression Omnibus database. Next, differentially expressed genes (DEGs) and differentially methylated genes (DMGs) between PD patients and healthy controls were identified. Least absolute shrinkage and selection operator cox regression analysis was carried out to construct a diagnostic signature based on the overlapped genes. And, the receiver operating characteristic (ROC) curves were drawn and the area under the curve (AUC) was used to assess the diagnostic performance of the signature in both the training and testing datasets. Finally, gene ontology and gene set enrichment analysis were subsequently carried out to explore the underlying mechanisms.ResultsWe obtained a total of 9,596 DMGs, 1,058 DEGs, and 237 overlapped genes in the whole blood between PD patients and healthy controls. Eight methylation-driven genes (HIST1H4L, CDC42EP3, KIT, GNLY, SLC22A1, GCM1, INO80B, and ARHGAP26) were identified to construct the gene expression signature. The AUCs in predicting PD patients were 0.84 and 0.76 in training dataset and testing dataset, respectively. Additionally, eight methylation-altered CpGs were also identified to construct the CpGs signature which showed a similarly robust diagnostic capability, with AUCs of 0.8 and 0.73 in training dataset and testing dataset, respectively.ConclusionWe conducted an integrated analysis of the gene expression and DNA methylation data, and constructed a methylation-driven genes signature and a methylation-altered CpGs signature to distinguish the patients with PD from healthy controls. Both of them had a robust prediction power and provide a new insight into personalized diagnostic and therapeutic strategies for PD.
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Affiliation(s)
- Ding Li
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
- Henan Engineering Research Center for Tumor Precision Medicine and Comprehensive Evaluation, Henan Cancer Hospital, Zhengzhou, China
- Henan Provincial Key Laboratory of Anticancer Drug Research, Henan Cancer Hospital, Zhengzhou, China
| | - Jiaming Liang
- Department of Internal Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Wenbin Guo
- Department of Pathology, Pingtan Comprehensive Experimental Area Hospital, Fuzhou, China
| | - Yongna Zhang
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
- Henan Engineering Research Center for Tumor Precision Medicine and Comprehensive Evaluation, Henan Cancer Hospital, Zhengzhou, China
- Henan Provincial Key Laboratory of Anticancer Drug Research, Henan Cancer Hospital, Zhengzhou, China
| | - Xuan Wu
- Academy of Medical Science, Zhengzhou University, Zhengzhou, China
- *Correspondence: Wenzhou Zhang,
| | - Wenzhou Zhang
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
- Henan Engineering Research Center for Tumor Precision Medicine and Comprehensive Evaluation, Henan Cancer Hospital, Zhengzhou, China
- Henan Provincial Key Laboratory of Anticancer Drug Research, Henan Cancer Hospital, Zhengzhou, China
- Xuan Wu,
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28
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Investigating the role of DNMT1 gene expression on myocardial ischemia reperfusion injury in rat and associated changes in mitochondria. BIOCHIMICA ET BIOPHYSICA ACTA. BIOENERGETICS 2022; 1863:148566. [PMID: 35489443 DOI: 10.1016/j.bbabio.2022.148566] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 04/13/2022] [Accepted: 04/18/2022] [Indexed: 12/31/2022]
Abstract
Altered DNA methylation and mitochondrial dysfunction are the two key features of myocardial ischemia reperfusion injury (I/R), but their association with I/R remains unknown. In the present study, the relationship between DNA methyl transferase1 (DNMT1), the key methylation gene, and the mitochondrial quality control genes in rat heart during I/R was explored. We used the Langendorff rat heart model with 30 min of ischemia followed by 60 min of reperfusion and subsequent inhibition of DNMT1 with 5-azacytidine to evaluate the role of DNA methylation in I/R. Reperfusion significantly increased the expression of the DNMT1 gene, enzyme activity, and global DNA methylation levels, along with decreased mitochondrial copy, electron transport chain (ETC) activities, and ATP level. This was in agreement with the significant downregulation of 11 mitochondrial genes PGC-1α, TFAM, POLG, MFN1 and MFN2, FIS1, PARKIN, OPTN, ND1, ND4L, Cyt B and COX1 in I/R induced rat hearts. The expression pattern of the mitochondrial genes PGC-1α, TFAM, ND1 and Cyt B showed a significant negative correlation with DNMT1 expression. Rate pressure product, index of cardiac performance negatively correlated with DNMT1 expression (r = -0.8231, p = 0.0456). However, DNMT1 inhibited rat hearts via 5-azacytidine significantly improved the heart from I/R injury and reversed the I/R associated changes in the gene expression of TFAM, POLG, PGC-1α, ND1, COX1 and Cyt B, and improved the overall mtDNA copies, with a subsequent improvement in the ETC enzyme activity and ATP levels. To conclude, I/R augmented the DNMT1 activity with a subsequent increase in cardiac injury via downregulating the mitochondrial functional genes.
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29
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Palese F, Pontis S, Realini N, Torrens A, Ahmed F, Assogna F, Pellicano C, Bossù P, Spalletta G, Green K, Piomelli D. Targeting NAAA counters dopamine neuron loss and symptom progression in mouse models of parkinsonism. Pharmacol Res 2022; 182:106338. [PMID: 35781057 PMCID: PMC9733952 DOI: 10.1016/j.phrs.2022.106338] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/19/2022] [Accepted: 06/29/2022] [Indexed: 12/13/2022]
Abstract
The lysosomal cysteine hydrolase N-acylethanolamine acid amidase (NAAA) deactivates palmitoylethanolamide (PEA), a lipid-derived PPAR-α agonist that is critically involved in the control of pain and inflammation. In this study, we asked whether NAAA-regulated PEA signaling might contribute to dopamine neuron degeneration and parkinsonism induced by the mitochondrial neurotoxins, 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In vitro experiments showed that 6-OHDA and MPTP enhanced NAAA expression and lowered PEA content in human SH-SY5Y cells. A similar effect was observed in mouse midbrain dopamine neurons following intra-striatal 6-OHDA injection. Importantly, deletion of the Naaa gene or pharmacological inhibition of NAAA activity substantially attenuated both dopamine neuron death and parkinsonian symptoms in mice treated with 6-OHDA or MPTP. Moreover, NAAA expression was elevated in postmortem brain cortex and premortem blood-derived exosomes from persons with Parkinson's disease compared to age-matched controls. The results identify NAAA-regulated PEA signaling as a molecular control point for dopaminergic neuron survival and a potential target for neuroprotective intervention.
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Affiliation(s)
- Francesca Palese
- Department of Anatomy and Neurobiology University of California Irvine, 92697-1275 CA, USA
| | - Silvia Pontis
- Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, 16163 Genoa, Italy
| | - Natalia Realini
- Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, 16163 Genoa, Italy
| | - Alexa Torrens
- Department of Anatomy and Neurobiology University of California Irvine, 92697-1275 CA, USA
| | - Faizy Ahmed
- Department of Anatomy and Neurobiology University of California Irvine, 92697-1275 CA, USA
| | - Francesca Assogna
- Laboratorio di Neuropsichiatria, IRCCS Santa Lucia Foundation, 00179 Rome, Italy
| | - Clelia Pellicano
- Laboratorio di Neuropsichiatria, IRCCS Santa Lucia Foundation, 00179 Rome, Italy
| | - Paola Bossù
- Laboratorio di Neuropsichiatria, IRCCS Santa Lucia Foundation, 00179 Rome, Italy
| | - Gianfranco Spalletta
- Laboratorio di Neuropsichiatria, IRCCS Santa Lucia Foundation, 00179 Rome, Italy
| | - Kim Green
- Department of Neurobiology and Behavior, University of California Irvine, 92697-1275 CA, USA
| | - Daniele Piomelli
- Department of Anatomy and Neurobiology University of California Irvine, 92697-1275 CA, USA,Department of Pharmaceutical Sciences, University of California Irvine, 92697-1275 CA, USA,Department of Biological Chemistry, University of California Irvine, 92697-1275 CA, USA
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30
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The role of NURR1 in metabolic abnormalities of Parkinson's disease. Mol Neurodegener 2022; 17:46. [PMID: 35761385 PMCID: PMC9235236 DOI: 10.1186/s13024-022-00544-w] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 05/21/2022] [Indexed: 11/30/2022] Open
Abstract
A constant metabolism and energy supply are crucial to all organs, particularly the brain. Age-dependent neurodegenerative diseases, such as Parkinson’s disease (PD), are associated with alterations in cellular metabolism. These changes have been recognized as a novel hot topic that may provide new insights to help identify risk in the pre-symptomatic phase of the disease, understand disease pathogenesis, track disease progression, and determine critical endpoints. Nuclear receptor-related factor 1 (NURR1), an orphan member of the nuclear receptor superfamily of transcription factors, is a major risk factor in the pathogenesis of PD, and changes in NURR1 expression can have a detrimental effect on cellular metabolism. In this review, we discuss recent evidence that suggests a vital role of NURR1 in dopaminergic (DAergic) neuron development and the pathogenesis of PD. The association between NURR1 and cellular metabolic abnormalities and its implications for PD therapy have been further highlighted.
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31
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Vesga-Jiménez DJ, Martin C, Barreto GE, Aristizábal-Pachón AF, Pinzón A, González J. Fatty Acids: An Insight into the Pathogenesis of Neurodegenerative Diseases and Therapeutic Potential. Int J Mol Sci 2022; 23:2577. [PMID: 35269720 PMCID: PMC8910658 DOI: 10.3390/ijms23052577] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 01/12/2022] [Accepted: 01/20/2022] [Indexed: 12/13/2022] Open
Abstract
One of the most common lipids in the human body is palmitic acid (PA), a saturated fatty acid with essential functions in brain cells. PA is used by cells as an energy source, besides being a precursor of signaling molecules and protein tilting across the membrane. Although PA plays physiological functions in the brain, its excessive accumulation leads to detrimental effects on brain cells, causing lipotoxicity. This mechanism involves the activation of toll-like receptors (TLR) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways, with the consequent release of pro-inflammatory cytokines, increased production of reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, and autophagy impairment. Importantly, some of the cellular changes induced by PA lead to an augmented susceptibility to the development of Alzheimer's and Parkinson´s diseases. Considering the complexity of the response to PA and the intrinsic differences of the brain, in this review, we provide an overview of the molecular and cellular effects of PA on different brain cells and their possible relationships with neurodegenerative diseases (NDs). Furthermore, we propose the use of other fatty acids, such as oleic acid or linoleic acid, as potential therapeutic approaches against NDs, as these fatty acids can counteract PA's negative effects on cells.
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Affiliation(s)
- Diego Julián Vesga-Jiménez
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogota 110231, Colombia; (D.J.V.-J.); (A.F.A.-P.)
- Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Atlanta, GA 30329, USA;
| | - Cynthia Martin
- Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Atlanta, GA 30329, USA;
| | - George E. Barreto
- Department of Biological Sciences, University of Limerick, V94 T9PX Limerick, Ireland;
- Health Research Institute, University of Limerick, V94 T9PX Limerick, Ireland
| | - Andrés Felipe Aristizábal-Pachón
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogota 110231, Colombia; (D.J.V.-J.); (A.F.A.-P.)
| | - Andrés Pinzón
- Laboratorio de Bioinformática y Biología de Sistemas, Universidad Nacional de Colombia, Bogota 111321, Colombia;
| | - Janneth González
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogota 110231, Colombia; (D.J.V.-J.); (A.F.A.-P.)
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Kaur G, Rathod SSS, Ghoneim MM, Alshehri S, Ahmad J, Mishra A, Alhakamy NA. DNA Methylation: A Promising Approach in Management of Alzheimer's Disease and Other Neurodegenerative Disorders. BIOLOGY 2022; 11:90. [PMID: 35053088 PMCID: PMC8773419 DOI: 10.3390/biology11010090] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 01/03/2022] [Accepted: 01/04/2022] [Indexed: 12/13/2022]
Abstract
DNA methylation, in the mammalian genome, is an epigenetic modification that involves the transfer of a methyl group on the C5 position of cytosine to derive 5-methylcytosine. The role of DNA methylation in the development of the nervous system and the progression of neurodegenerative diseases such as Alzheimer's disease has been an interesting research area. Furthermore, mutations altering DNA methylation affect neurodevelopmental functions and may cause the progression of several neurodegenerative diseases. Epigenetic modifications in neurodegenerative diseases are widely studied in different populations to uncover the plausible mechanisms contributing to the development and progression of the disease and detect novel biomarkers for early prognosis and future pharmacotherapeutic targets. In this manuscript, we summarize the association of DNA methylation with the pathogenesis of the most common neurodegenerative diseases, such as, Alzheimer's disease, Parkinson's disease, Huntington diseases, and amyotrophic lateral sclerosis, and discuss the potential of DNA methylation as a potential biomarker and therapeutic tool for neurogenerative diseases.
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Affiliation(s)
- Gagandeep Kaur
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411, Punjab, India; (G.K.); (S.S.S.R.)
| | - Suraj Singh S. Rathod
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411, Punjab, India; (G.K.); (S.S.S.R.)
| | - Mohammed M. Ghoneim
- Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Ad Diriyah 13713, Saudi Arabia;
| | - Sultan Alshehri
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia;
| | - Javed Ahmad
- Department of Pharmaceutics, College of Pharmacy, Najran University, Najran 11001, Saudi Arabia;
| | - Awanish Mishra
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)—Guwahati, Changsari, Kamrup 781101, Assam, India
| | - Nabil A. Alhakamy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
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33
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Panes JD, Wendt A, Ramirez-Molina O, Castro PA, Fuentealba J. Deciphering the role of PGC-1α in neurological disorders: from mitochondrial dysfunction to synaptic failure. Neural Regen Res 2022; 17:237-245. [PMID: 34269182 PMCID: PMC8463972 DOI: 10.4103/1673-5374.317957] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
The onset and mechanisms underlying neurodegenerative diseases remain uncertain. The main features of neurodegenerative diseases have been related with cellular and molecular events like neuronal loss, mitochondrial dysfunction and aberrant accumulation of misfolded proteins or peptides in specific areas of the brain. The most prevalent neurodegenerative diseases belonging to age-related pathologies are Alzheimer's disease, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis. Interestingly, mitochondrial dysfunction has been observed to occur during the early onset of several neuropathological events associated to neurodegenerative diseases. The master regulator of mitochondrial quality control and energetic metabolism is the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Additionally, it has been observed that PGC-1α appears to be a key factor in maintaining neuronal survival and synaptic transmission. In fact, PGC-1α downregulation in different brain areas (hippocampus, substantia nigra, cortex, striatum and spinal cord) that occurs in function of neurological damage including oxidative stress, neuronal loss, and motor disorders has been seen in several animal and cellular models of neurodegenerative diseases. Current evidence indicates that PGC-1α upregulation may serve as a potent therapeutic approach against development and progression of neuronal damage. Remarkably, increasing evidence shows that PGC-1α deficient mice have neurodegenerative diseases-like features, as well as neurological abnormalities. Finally, we discuss recent studies showing novel specific PGC-1α isoforms in the central nervous system that appear to exert a key role in the age of onset of neurodegenerative diseases and have a neuroprotective function in the central nervous system, thus opening a new molecular strategy for treatment of neurodegenerative diseases. The purpose of this review is to provide an up-to-date overview of the PGC-1α role in the physiopathology of neurodegenerative diseases, as well as establish the importance of PGC-1α function in synaptic transmission and neuronal survival.
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Affiliation(s)
- Jessica D Panes
- Laboratorio de Screening de Compuestos Neuroactivos (LSCN), Departamento de Fisiología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Aline Wendt
- Laboratorio de Screening de Compuestos Neuroactivos (LSCN), Departamento de Fisiología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Oscar Ramirez-Molina
- Laboratorio de Screening de Compuestos Neuroactivos (LSCN), Departamento de Fisiología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Patricio A Castro
- Departamento de Fisiología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Jorge Fuentealba
- Laboratorio de Screening de Compuestos Neuroactivos (LSCN), Departamento de Fisiología; Centro de Investigaciones Avanzadas en Biomedicina (CIAB-UdeC), Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
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34
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Birla H, Keswani C, Singh SS, Zahra W, Dilnashin H, Rathore AS, Singh R, Rajput M, Keshri P, Singh SP. Unraveling the Neuroprotective Effect of Tinospora cordifolia in a Parkinsonian Mouse Model through the Proteomics Approach. ACS Chem Neurosci 2021; 12:4319-4335. [PMID: 34747594 DOI: 10.1021/acschemneuro.1c00481] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Stress-induced dopaminergic (DAergic) neuronal death in the midbrain region is the primary cause of Parkinson's disease (PD). Following the discovery of l-dopa, multiple drugs have been developed to improve the lifestyle of PD patients; however, none have been suitable for clinical use due to their multiple side effects. Tinospora cordifolia has been used in traditional medicines to treat neurodegenerative diseases. Previously, we reported the neuroprotective role of Tc via inhibition of NF-κB-associated proinflammatory cytokines against MPTP-intoxicated Parkinsonian mice. In the present study, we investigated the neuroprotective molecular mechanism of Tc in a rotenone (ROT)-intoxicated mouse model, using a proteomics approach. Mice were pretreated with Tc extract by oral administration, followed by ROT intoxication. Behavioral tests were performed to check motor functions of mice. Protein was isolated, and label-free quantification (LFQ) was carried out to identify differentially expressed protein (DEP) in control vs PD and PD vs treatment groups. Results were validated by qRT-PCR with the expression of target genes correlating with the proteomics data. In this study, we report 800 DEPs in control vs PD and 133 in PD vs treatment groups. In silico tools demonstrate significant enrichment of biochemical and molecular pathways with DEPs, which are known to be important for PD progression including mitochondrial gene expression, PD pathways, TGF-β signaling, and Alzheimer's disease. This study provides novel insights into the PD progression as well as new therapeutic targets. More importantly, it demonstrates that Tc can exert therapeutic effects by regulating multiple pathways, resulting in neuroprotection.
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Affiliation(s)
- Hareram Birla
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India
| | - Chetan Keswani
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India
| | - Saumitra Sen Singh
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India
| | - Walia Zahra
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India
| | - Hagera Dilnashin
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India
| | - Aaina Singh Rathore
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India
| | - Richa Singh
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India
| | - Monika Rajput
- Department of Bioinformatics, Mahila Maha Vidhyalaya, Banaras Hindu University, Varanasi 221005, India
| | - Priyanka Keshri
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India
| | - Surya Pratap Singh
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India
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35
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Xu S, Zhang X, Liu C, Liu Q, Chai H, Luo Y, Li S. Role of Mitochondria in Neurodegenerative Diseases: From an Epigenetic Perspective. Front Cell Dev Biol 2021; 9:688789. [PMID: 34513831 PMCID: PMC8429841 DOI: 10.3389/fcell.2021.688789] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 08/10/2021] [Indexed: 12/18/2022] Open
Abstract
Mitochondria, the centers of energy metabolism, have been shown to participate in epigenetic regulation of neurodegenerative diseases. Epigenetic modification of nuclear genes encoding mitochondrial proteins has an impact on mitochondria homeostasis, including mitochondrial biogenesis, and quality, which plays role in the pathogenesis of neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. On the other hand, intermediate metabolites regulated by mitochondria such as acetyl-CoA and NAD+, in turn, may regulate nuclear epigenome as the substrate for acetylation and a cofactor of deacetylation, respectively. Thus, mitochondria are involved in epigenetic regulation through bidirectional communication between mitochondria and nuclear, which may provide a new strategy for neurodegenerative diseases treatment. In addition, emerging evidence has suggested that the abnormal modification of mitochondria DNA contributes to disease development through mitochondria dysfunction. In this review, we provide an overview of how mitochondria are involved in epigenetic regulation and discuss the mechanisms of mitochondria in regulation of neurodegenerative diseases from epigenetic perspective.
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Affiliation(s)
- Sutong Xu
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopedic Department of Tongji Hospital, Tongji University School of Medicine, Shanghai, China.,Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xi Zhang
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopedic Department of Tongji Hospital, Tongji University School of Medicine, Shanghai, China.,Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Chenming Liu
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopedic Department of Tongji Hospital, Tongji University School of Medicine, Shanghai, China.,Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qiulu Liu
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopedic Department of Tongji Hospital, Tongji University School of Medicine, Shanghai, China.,Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Huazhen Chai
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopedic Department of Tongji Hospital, Tongji University School of Medicine, Shanghai, China.,Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yuping Luo
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopedic Department of Tongji Hospital, Tongji University School of Medicine, Shanghai, China.,Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Siguang Li
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopedic Department of Tongji Hospital, Tongji University School of Medicine, Shanghai, China.,Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
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36
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Wu TT, Liu T, Li X, Chen YJ, Chen TJ, Zhu XY, Chen JL, Li Q, Liu Y, Feng Y, Wu YC. TET2-mediated Cdkn2A DNA hydroxymethylation in midbrain dopaminergic neuron injury of Parkinson's disease. Hum Mol Genet 2021; 29:1239-1252. [PMID: 32037456 DOI: 10.1093/hmg/ddaa022] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 01/03/2020] [Accepted: 02/03/2020] [Indexed: 12/31/2022] Open
Abstract
It has been reported that abnormal epigenetic modification is associated with the occurrence of Parkinson's disease (PD). Here, we found that a ten-eleven translocation 2 (TET2), a staff of the DNA hydroxylases family, was increased in dopaminergic neurons in vitro and in vivo. Genome-wide mapping of DNA 5-hydroxymethylcytosine (5-hmC)-sequencing has revealed an aberrant epigenome 5-hmC landscape in 1-methyl-4-phenylpyridinium iodide (MPP+)-induced SH-SY5Y cells. The TET family of DNA hydroxylases could reverse DNA methylation by oxidization of 5-methylcytosine (5-mC) to 5-hmC. However, the relationship between modification of DNA hydroxymethylation and the pathogenesis of PD is not clear. According to the results of 5-hmC-sequencing studies, 5-hmC was associated with gene-rich regions in the genomes related to cell cycle, especially gene-cyclin-dependent kinase inhibitor 2A (Cdkn2A). Downregulation of TET2 expression could significantly rescue MPP+-stimulated SH-SY5Y cell damage and cell cycle arrest. Meanwhile, knockdown of Tet2 expression in the substantia nigra pars compacta of MPTP-induced PD mice resulted in attenuated MPTP-induced motor deficits and dopaminergic neuronal injury via p16 suppression. In this study, we demonstrated a critical function of TET2 in PD development via the CDKN2A activity-dependent epigenetic pathway, suggesting a potential new strategy for epigenetic therapy.
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Affiliation(s)
- Ting-Ting Wu
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Te Liu
- Shanghai Geriatric Institute of Chinese Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200031, P.R. China
| | - Xuan Li
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Ya-Jing Chen
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Tian-Jiao Chen
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Xiao-Ying Zhu
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Jiu-Lin Chen
- Shanghai Geriatric Institute of Chinese Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200031, P.R. China
| | - Qing Li
- The State Key Laboratory of Medical Neurobiology, The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
| | - Ye Liu
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Ya Feng
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Yun-Cheng Wu
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
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37
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Jo A, Lee Y, Kam TI, Kang SU, Neifert S, Karuppagounder SS, Khang R, Kang H, Park H, Chou SC, Oh S, Jiang H, Swing DA, Ham S, Pirooznia S, Umanah GKE, Mao X, Kumar M, Ko HS, Kang HC, Lee BD, Lee YI, Andrabi SA, Park CH, Lee JY, Kim H, Kim H, Kim H, Cho JW, Paek SH, Na CH, Tessarollo L, Dawson VL, Dawson TM, Shin JH. PARIS farnesylation prevents neurodegeneration in models of Parkinson's disease. Sci Transl Med 2021; 13:13/604/eaax8891. [PMID: 34321320 PMCID: PMC9990146 DOI: 10.1126/scitranslmed.aax8891] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 12/09/2020] [Accepted: 05/20/2021] [Indexed: 12/18/2022]
Abstract
Accumulation of the parkin-interacting substrate (PARIS; ZNF746), due to inactivation of parkin, contributes to Parkinson's disease (PD) through repression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α; PPARGC1A) activity. Here, we identify farnesol as an inhibitor of PARIS. Farnesol promoted the farnesylation of PARIS, preventing its repression of PGC-1α via decreasing PARIS occupancy on the PPARGC1A promoter. Farnesol prevented dopaminergic neuronal loss and behavioral deficits via farnesylation of PARIS in PARIS transgenic mice, ventral midbrain transduction of AAV-PARIS, adult conditional parkin KO mice, and the α-synuclein preformed fibril model of sporadic PD. PARIS farnesylation is decreased in the substantia nigra of patients with PD, suggesting that reduced farnesylation of PARIS may play a role in PD. Thus, farnesol may be beneficial in the treatment of PD by enhancing the farnesylation of PARIS and restoring PGC-1α activity.
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Affiliation(s)
- Areum Jo
- Department of Pharmacology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 16419, South Korea.,Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Yunjong Lee
- Department of Pharmacology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 16419, South Korea.,Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.,Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA
| | - Tae-In Kam
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Sung-Ung Kang
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.,Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA
| | - Stewart Neifert
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.,Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA
| | - Senthilkumar S Karuppagounder
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.,Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA
| | - Rin Khang
- Department of Pharmacology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 16419, South Korea
| | - Hojin Kang
- Department of Pharmacology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 16419, South Korea.,Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Hyejin Park
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Shih-Ching Chou
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.,Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA.,Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Sungtaek Oh
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Haisong Jiang
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.,Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA
| | - Deborah A Swing
- Neural Development Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21705, USA
| | - Sangwoo Ham
- Department of Pharmacology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 16419, South Korea
| | - Sheila Pirooznia
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.,Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA
| | - George K E Umanah
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.,Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA
| | - Xiaobo Mao
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.,Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA
| | - Manoj Kumar
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA
| | - Han Seok Ko
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.,Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA
| | - Ho Chul Kang
- Department of Physiology, Ajou University School of Medicine, Suwon 16499, South Korea
| | - Byoung Dae Lee
- Neurodegeneration Control Research Center, Department of Neuroscience, Department of Physiology, Kyung Hee University School of Medicine, Seoul 02447, South Korea
| | - Yun-Il Lee
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Shaida A Andrabi
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Chi-Hu Park
- Research Core Facility, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 16419, South Korea
| | - Ji-Yeong Lee
- Department of Pharmacology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 16419, South Korea
| | - Hanna Kim
- Department of Pharmacology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 16419, South Korea
| | - Hyein Kim
- Department of Pharmacology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 16419, South Korea.,Research Core Facility, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 16419, South Korea
| | - Hyojung Kim
- Department of Pharmacology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 16419, South Korea
| | - Jin Whan Cho
- Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea
| | - Sun Ha Paek
- Department of Neurosurgery, Seoul National University College of Medicine, Seoul 03080, South Korea
| | - Chan Hyun Na
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Lino Tessarollo
- Neural Development Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21705, USA
| | - Valina L Dawson
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.,Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA.,Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Ted M Dawson
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. .,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.,Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA.,Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Joo-Ho Shin
- Department of Pharmacology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 16419, South Korea. .,Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Samsung Medical Center, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Seoul 06351, South Korea
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38
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Murthy M, Cheng YY, Holton JL, Bettencourt C. Neurodegenerative movement disorders: An epigenetics perspective and promise for the future. Neuropathol Appl Neurobiol 2021; 47:897-909. [PMID: 34318515 PMCID: PMC9291277 DOI: 10.1111/nan.12757] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 07/12/2021] [Indexed: 02/02/2023]
Abstract
Neurodegenerative movement disorders (NMDs) are age‐dependent disorders that are characterised by the degeneration and loss of neurons, typically accompanied by pathological accumulation of different protein aggregates in the brain, which lead to motor symptoms. NMDs include Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, and Huntington's disease, among others. Epigenetic modifications are responsible for functional gene regulation during development, adult life and ageing and have progressively been implicated in complex diseases such as cancer and more recently in neurodegenerative diseases, such as NMDs. DNA methylation is by far the most widely studied epigenetic modification and consists of the reversible addition of a methyl group to the DNA without changing the DNA sequence. Although this research field is still in its infancy in relation to NMDs, an increasing number of studies point towards a role for DNA methylation in disease processes. This review addresses recent advances in epigenetic and epigenomic research in NMDs, with a focus on human brain DNA methylation studies. We discuss the current understanding of the DNA methylation changes underlying these disorders, the potential for use of these DNA modifications in peripheral tissues as biomarkers in early disease detection, classification and progression as well as a promising role in future disease management and therapy.
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Affiliation(s)
- Megha Murthy
- Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, UK.,Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK
| | - Yun Yung Cheng
- Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, UK
| | - Janice L Holton
- Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, UK.,Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK
| | - Conceição Bettencourt
- Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, UK.,Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK
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39
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Ganguly U, Singh S, Pal S, Prasad S, Agrawal BK, Saini RV, Chakrabarti S. Alpha-Synuclein as a Biomarker of Parkinson's Disease: Good, but Not Good Enough. Front Aging Neurosci 2021; 13:702639. [PMID: 34305577 PMCID: PMC8298029 DOI: 10.3389/fnagi.2021.702639] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 06/07/2021] [Indexed: 12/15/2022] Open
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disorder of the elderly, presenting primarily with symptoms of motor impairment. The disease is diagnosed most commonly by clinical examination with a great degree of accuracy in specialized centers. However, in some cases, non-classical presentations occur when it may be difficult to distinguish the disease from other types of degenerative or non-degenerative movement disorders with overlapping symptoms. The diagnostic difficulty may also arise in patients at the early stage of PD. Thus, a biomarker could help clinicians circumvent such problems and help them monitor the improvement in disease pathology during anti-parkinsonian drug trials. This review first provides a brief overview of PD, emphasizing, in the process, the important role of α-synuclein in the pathogenesis of the disease. Various attempts made by the researchers to develop imaging, genetic, and various biochemical biomarkers for PD are then briefly reviewed to point out the absence of a definitive biomarker for this disorder. In view of the overwhelming importance of α-synuclein in the pathogenesis, a detailed analysis is then made of various studies to establish the biomarker potential of this protein in PD; these studies measured total α-synuclein, oligomeric, and post-translationally modified forms of α-synuclein in cerebrospinal fluid, blood (plasma, serum, erythrocytes, and circulating neuron-specific extracellular vesicles) and saliva in combination with certain other proteins. Multiple studies also examined the accumulation of α-synuclein in various forms in PD in the neural elements in the gut, submandibular glands, skin, and the retina. The measurements of the levels of certain forms of α-synuclein in some of these body fluids or their components or peripheral tissues hold a significant promise in establishing α-synuclein as a definitive biomarker for PD. However, many methodological issues related to detection and quantification of α-synuclein have to be resolved, and larger cross-sectional and follow-up studies with controls and patients of PD, parkinsonian disorders, and non-parkinsonian movement disorders are to be undertaken.
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Affiliation(s)
- Upasana Ganguly
- Department of Biochemistry and Central Research Laboratory, Maharishi Markandeshwar Institute of Medical Sciences and Research, Maharishi Markandeshwar Deemed University, Ambala, India
| | - Sukhpal Singh
- Department of Biochemistry and Central Research Laboratory, Maharishi Markandeshwar Institute of Medical Sciences and Research, Maharishi Markandeshwar Deemed University, Ambala, India
| | - Soumya Pal
- Department of Biochemistry and Central Research Laboratory, Maharishi Markandeshwar Institute of Medical Sciences and Research, Maharishi Markandeshwar Deemed University, Ambala, India
| | - Suvarna Prasad
- Department of Biochemistry and Central Research Laboratory, Maharishi Markandeshwar Institute of Medical Sciences and Research, Maharishi Markandeshwar Deemed University, Ambala, India
| | - Bimal K. Agrawal
- Department of General Medicine, Maharishi Markandeshwar Institute of Medical Sciences and Research, Maharishi Markandeshwar Deemed University, Ambala, India
| | - Reena V. Saini
- Department of Biotechnology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar Deemed University, Ambala, India
| | - Sasanka Chakrabarti
- Department of Biochemistry and Central Research Laboratory, Maharishi Markandeshwar Institute of Medical Sciences and Research, Maharishi Markandeshwar Deemed University, Ambala, India
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P P, Justin A, Ananda Kumar TD, Chinaswamy M, Kumar BRP. Glitazones Activate PGC-1α Signaling via PPAR-γ: A Promising Strategy for Antiparkinsonism Therapeutics. ACS Chem Neurosci 2021; 12:2261-2272. [PMID: 34125534 DOI: 10.1021/acschemneuro.1c00085] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Understanding various aspects of Parkinson's disease (PD) by researchers could lead to a better understanding of the disease and provide treatment alternatives that could significantly improve the quality of life of patients suffering from neurodegenerative disorders. Significant progress has been made in recent years toward this goal, but there is yet no available treatment with confirmed neuroprotective effects. Recent studies have shown the potential of PPARγ agonists, which are the ligand activated transcriptional factor of the nuclear hormone superfamily, as therapeutic targets for various neurodegenerative disorders. The activation of central PGC-1α mediates the potential role against neurogenerative diseases like PD, Huntington's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. Further understanding the mechanism of neurodegeneration and the role of glitazones in the activation of PGC-1α signaling could lead to a novel therapeutic interventions against PD. Keeping this aspect in focus, the present review highlights the pathogenic mechanism of PD and the role of glitazones in the activation of PGC-1α via PPARγ for the treatment of neurodegenerative disorders.
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Affiliation(s)
- Prabitha P
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru, Karnataka 570 015, India
| | - Antony Justin
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamilnadu 643 001, India
| | - T. Durai Ananda Kumar
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru, Karnataka 570 015, India
| | - Mithuna Chinaswamy
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru, Karnataka 570 015, India
| | - B. R. Prashantha Kumar
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru, Karnataka 570 015, India
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Zhang HQ, Wang JY, Li ZF, Cui L, Huang SS, Zhu LB, Sun Y, Yang R, Fan HH, Zhang X, Zhu JH. DNA Methyltransferase 1 Is Dysregulated in Parkinson's Disease via Mediation of miR-17. Mol Neurobiol 2021; 58:2620-2633. [PMID: 33483902 DOI: 10.1007/s12035-021-02298-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 01/14/2021] [Indexed: 12/12/2022]
Abstract
Aberrant DNA methylation is closely associated with the pathogenesis of Parkinson's disease (PD). DNA methyltransferases (DNMTs) are the enzymes for establishment and maintenance of DNA methylation patterns. It has not been clearly defined how DNMTs respond in PD and what mechanisms are associated. Models of PD were established by treatment of five different neurotoxins in cells and intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice. Plasma samples of PD patients were also used. Western blot, real-time PCR, immunostaining, and/or luciferase reporter were employed. DNA methylation was analyzed by the bisulfite sequencing analysis. Protein expression of DNMT1, but not of DNMT3A and DNMT3B, was reduced in the cellular and mouse models of PD. Paradoxically, mRNA levels of DNMT1 were increased in these models. After ruling out the possibility of protein degradation, we screened a set of miRNAs that potentially targeted DNMT1 3'-UTR by luciferase reporters and expression abundancies. miR-17 was identified for further investigation with miR-19a of low expression as a parallel comparison. Although exogenous transfection of either miR-17 or miR-19a mimics could inhibit DNMT1 expression, results of miRNA inhibitors showed that miR-17, but not miR-19a, endogenously regulated DNMT1 and the subsequent DNA methylation. Furthermore, levels of miR-17 were elevated in the neurotoxin-induced PD models and the plasma of PD patients. This study demonstrates that the miR-17-mediated DNMT1 downregulation underlies the aberrant DNA methylation in PD. Our results provide a link bridging environmental insults and epigenetic changes and implicate miR-17 in therapeutical modulation of DNA methylation in PD.
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Affiliation(s)
- Hong-Qiu Zhang
- Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Department of Geriatrics and Neurology, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
| | - Jian-Yong Wang
- Department of Geriatrics and Neurology, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
| | - Zhao-Feng Li
- Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Lei Cui
- Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Shi-Shi Huang
- Department of Geriatrics and Neurology, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
| | - Lan-Bing Zhu
- Department of Geriatrics and Neurology, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
| | - Yue Sun
- Department of Geriatrics and Neurology, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
| | - Rui Yang
- Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Nelson Institute of Environmental Medicine, New York University School of Medicine, 341 East 25th Street, New York, NY, 10010, USA
| | - Hui-Hui Fan
- Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Xiong Zhang
- Department of Geriatrics and Neurology, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China.
| | - Jian-Hong Zhu
- Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
- Department of Geriatrics and Neurology, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China.
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Ray B, Mahalakshmi AM, Tuladhar S, Bhat A, Srinivasan A, Pellegrino C, Kannan A, Bolla SR, Chidambaram SB, Sakharkar MK. "Janus-Faced" α-Synuclein: Role in Parkinson's Disease. Front Cell Dev Biol 2021; 9:673395. [PMID: 34124057 PMCID: PMC8194081 DOI: 10.3389/fcell.2021.673395] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Accepted: 04/15/2021] [Indexed: 01/03/2023] Open
Abstract
Parkinson's disease (PD) is a pathological condition characterized by the aggregation and the resultant presence of intraneuronal inclusions termed Lewy bodies (LBs) and Lewy neurites which are mainly composed of fibrillar α-synuclein (α-syn) protein. Pathogenic aggregation of α-syn is identified as the major cause of LBs deposition. Several mutations in α-syn showing varied aggregation kinetics in comparison to the wild type (WT) α-syn are reported in PD (A30P, E46K, H 50Q, G51D, A53E, and A53T). Also, the cell-to-cell spread of pathological α-syn plays a significant role in PD development. Interestingly, it has also been suggested that the pathology of PD may begin in the gastrointestinal tract and spread via the vagus nerve (VN) to brain proposing the gut-brain axis of α-syn pathology in PD. Despite multiple efforts, the behavior and functions of this protein in normal and pathological states (specifically in PD) is far from understood. Furthermore, the etiological factors responsible for triggering aggregation of this protein remain elusive. This review is an attempt to collate and present latest information on α-syn in relation to its structure, biochemistry and biophysics of aggregation in PD. Current advances in therapeutic efforts toward clearing the pathogenic α-syn via autophagy/lysosomal flux are also reviewed and reported.
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Affiliation(s)
- Bipul Ray
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru, India
- Centre for Experimental Pharmacology and Toxicology, Central Animal Facility, JSS Academy of Higher Education & Research, Mysuru, India
| | - Arehally M. Mahalakshmi
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru, India
| | - Sunanda Tuladhar
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru, India
- Centre for Experimental Pharmacology and Toxicology, Central Animal Facility, JSS Academy of Higher Education & Research, Mysuru, India
| | - Abid Bhat
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru, India
- Centre for Experimental Pharmacology and Toxicology, Central Animal Facility, JSS Academy of Higher Education & Research, Mysuru, India
| | - Asha Srinivasan
- Division of Nanoscience & Technology, Faculty of Life Sciences, JSS Academy of Higher Education & Research, Mysuru, India
| | - Christophe Pellegrino
- Institut National de la Santé et de la Recherche Médicale, Institute of Mediterranean Neurobiology, Aix-Marseille University, Marseille, France
| | - Anbarasu Kannan
- Department of Protein Chemistry and Technology, CSIR-Central Food Technological Research Institute, Mysuru, India
| | - Srinivasa Rao Bolla
- Department of Biomedical Sciences, School of Medicine, Nazarbayev University, Nur-Sultan City, Kazakhstan
| | - Saravana Babu Chidambaram
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru, India
- Centre for Experimental Pharmacology and Toxicology, Central Animal Facility, JSS Academy of Higher Education & Research, Mysuru, India
- Special Interest Group – Brain, Behaviour, and Cognitive Neurosciences Research, JSS Academy of Higher Education & Research, Mysuru, India
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Rasheed M, Liang J, Wang C, Deng Y, Chen Z. Epigenetic Regulation of Neuroinflammation in Parkinson's Disease. Int J Mol Sci 2021; 22:4956. [PMID: 34066949 PMCID: PMC8125491 DOI: 10.3390/ijms22094956] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 04/27/2021] [Accepted: 04/29/2021] [Indexed: 02/08/2023] Open
Abstract
Neuroinflammation is one of the most significant factors involved in the initiation and progression of Parkinson's disease. PD is a neurodegenerative disorder with a motor disability linked with various complex and diversified risk factors. These factors trigger myriads of cellular and molecular processes, such as misfolding defective proteins, oxidative stress, mitochondrial dysfunction, and neurotoxic substances that induce selective neurodegeneration of dopamine neurons. This neuronal damage activates the neuronal immune system, including glial cells and inflammatory cytokines, to trigger neuroinflammation. The transition of acute to chronic neuroinflammation enhances the susceptibility of inflammation-induced dopaminergic neuron damage, forming a vicious cycle and prompting an individual to PD development. Epigenetic mechanisms recently have been at the forefront of the regulation of neuroinflammatory factors in PD, proposing a new dawn for breaking this vicious cycle. This review examined the core epigenetic mechanisms involved in the activation and phenotypic transformation of glial cells mediated neuroinflammation in PD. We found that epigenetic mechanisms do not work independently, despite being coordinated with each other to activate neuroinflammatory pathways. In this regard, we attempted to find the synergic correlation and contribution of these epigenetic modifications with various neuroinflammatory pathways to broaden the canvas of underlying pathological mechanisms involved in PD development. Moreover, this study highlighted the dual characteristics (neuroprotective/neurotoxic) of these epigenetic marks, which may counteract PD pathogenesis and make them potential candidates for devising future PD diagnosis and treatment.
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Affiliation(s)
| | | | | | | | - Zixuan Chen
- School of Life Science, Beijing Institute of Technology, Beijing 100081, China; (M.R.); (J.L.); (C.W.); (Y.D.)
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Henderson AR, Wang Q, Meechoovet B, Siniard AL, Naymik M, De Both M, Huentelman MJ, Caselli RJ, Driver-Dunckley E, Dunckley T. DNA Methylation and Expression Profiles of Whole Blood in Parkinson's Disease. Front Genet 2021; 12:640266. [PMID: 33981329 PMCID: PMC8107387 DOI: 10.3389/fgene.2021.640266] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 03/16/2021] [Indexed: 12/20/2022] Open
Abstract
Parkinson’s disease (PD) is the second most common age-related neurodegenerative disease. It is presently only accurately diagnosed at an advanced stage by a series of motor deficits, which are predated by a litany of non-motor symptoms manifesting over years or decades. Aberrant epigenetic modifications exist across a range of diseases and are non-invasively detectable in blood as potential markers of disease. We performed comparative analyses of the methylome and transcriptome in blood from PD patients and matched controls. Our aim was to characterize DNA methylation and gene expression patterns in whole blood from PD patients as a foundational step toward the future goal of identifying molecular markers that could predict, accurately diagnose, or track the progression of PD. We found that differentially expressed genes (DEGs) were involved in the processes of transcription and mitochondrial function and that PD methylation profiles were readily distinguishable from healthy controls, even in whole-blood DNA samples. Differentially methylated regions (DMRs) were functionally varied, including near transcription factor nuclear transcription factor Y subunit alpha (NFYA), receptor tyrosine kinase DDR1, RING finger ubiquitin ligase (RNF5), acetyltransferase AGPAT1, and vault RNA VTRNA2-1. Expression quantitative trait methylation sites were found at long non-coding RNA PAX8-AS1 and transcription regulator ZFP57 among others. Functional epigenetic modules were highlighted by IL18R1, PTPRC, and ITGB2. We identified patterns of altered disease-specific DNA methylation and associated gene expression in whole blood. Our combined analyses extended what we learned from the DEG or DMR results alone. These studies provide a foundation to support the characterization of larger sample cohorts, with the goal of building a thorough, accurate, and non-invasive molecular PD biomarker.
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Affiliation(s)
- Adrienne R Henderson
- Neurodegenerative Disease Research Center, Biodesign Institute, Arizona State University, Tempe, AZ, United States
| | - Qi Wang
- Neurodegenerative Disease Research Center, Biodesign Institute, Arizona State University, Tempe, AZ, United States
| | - Bessie Meechoovet
- Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, United States
| | - Ashley L Siniard
- Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, United States
| | - Marcus Naymik
- Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, United States
| | - Matthew De Both
- Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, United States
| | - Matthew J Huentelman
- Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, United States
| | | | | | - Travis Dunckley
- Neurodegenerative Disease Research Center, Biodesign Institute, Arizona State University, Tempe, AZ, United States
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PGC-1s in the Spotlight with Parkinson's Disease. Int J Mol Sci 2021; 22:ijms22073487. [PMID: 33800548 PMCID: PMC8036867 DOI: 10.3390/ijms22073487] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/24/2021] [Accepted: 03/25/2021] [Indexed: 12/12/2022] Open
Abstract
Parkinson's disease is one of the most common neurodegenerative disorders worldwide, characterized by a progressive loss of dopaminergic neurons mainly localized in the substantia nigra pars compacta. In recent years, the detailed analyses of both genetic and idiopathic forms of the disease have led to a better understanding of the molecular and cellular pathways involved in PD, pointing to the centrality of mitochondrial dysfunctions in the pathogenic process. Failure of mitochondrial quality control is now considered a hallmark of the disease. The peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1) family acts as a master regulator of mitochondrial biogenesis. Therefore, keeping PGC-1 level in a proper range is fundamental to guarantee functional neurons. Here we review the major findings that tightly bond PD and PGC-1s, raising important points that might lead to future investigations.
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Acevedo N, Alashkar Alhamwe B, Caraballo L, Ding M, Ferrante A, Garn H, Garssen J, Hii CS, Irvine J, Llinás-Caballero K, López JF, Miethe S, Perveen K, Pogge von Strandmann E, Sokolowska M, Potaczek DP, van Esch BCAM. Perinatal and Early-Life Nutrition, Epigenetics, and Allergy. Nutrients 2021; 13:724. [PMID: 33668787 PMCID: PMC7996340 DOI: 10.3390/nu13030724] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 02/08/2021] [Accepted: 02/12/2021] [Indexed: 02/08/2023] Open
Abstract
Epidemiological studies have shown a dramatic increase in the incidence and the prevalence of allergic diseases over the last several decades. Environmental triggers including risk factors (e.g., pollution), the loss of rural living conditions (e.g., farming conditions), and nutritional status (e.g., maternal, breastfeeding) are considered major contributors to this increase. The influences of these environmental factors are thought to be mediated by epigenetic mechanisms which are heritable, reversible, and biologically relevant biochemical modifications of the chromatin carrying the genetic information without changing the nucleotide sequence of the genome. An important feature characterizing epigenetically-mediated processes is the existence of a time frame where the induced effects are the strongest and therefore most crucial. This period between conception, pregnancy, and the first years of life (e.g., first 1000 days) is considered the optimal time for environmental factors, such as nutrition, to exert their beneficial epigenetic effects. In the current review, we discussed the impact of the exposure to bacteria, viruses, parasites, fungal components, microbiome metabolites, and specific nutritional components (e.g., polyunsaturated fatty acids (PUFA), vitamins, plant- and animal-derived microRNAs, breast milk) on the epigenetic patterns related to allergic manifestations. We gave insight into the epigenetic signature of bioactive milk components and the effects of specific nutrition on neonatal T cell development. Several lines of evidence suggest that atypical metabolic reprogramming induced by extrinsic factors such as allergens, viruses, pollutants, diet, or microbiome might drive cellular metabolic dysfunctions and defective immune responses in allergic disease. Therefore, we described the current knowledge on the relationship between immunometabolism and allergy mediated by epigenetic mechanisms. The knowledge as presented will give insight into epigenetic changes and the potential of maternal and post-natal nutrition on the development of allergic disease.
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Affiliation(s)
- Nathalie Acevedo
- Institute for Immunological Research, University of Cartagena, Cartagena 130014, Colombia; (N.A.); (L.C.); (K.L.-C.); (J.F.L.)
| | - Bilal Alashkar Alhamwe
- Institute of Tumor Immunology, Clinic for Hematology, Oncology and Immunology, Center for Tumor Biology and Immunology, Philipps University Marburg, 35043 Marburg, Germany; (B.A.A.); (E.P.v.S.)
- College of Pharmacy, International University for Science and Technology (IUST), Daraa 15, Syria
| | - Luis Caraballo
- Institute for Immunological Research, University of Cartagena, Cartagena 130014, Colombia; (N.A.); (L.C.); (K.L.-C.); (J.F.L.)
| | - Mei Ding
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, 7265 Davos, Switzerland; (M.D.); (M.S.)
- Christine Kühne-Center for Allergy Research and Education, 7265 Davos, Switzerland
- Department of Allergology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Antonio Ferrante
- Department of Immunopathology, SA Pathology at the Women’s and Children’s Hospital, North Adelaide, SA 5006, Australia; (A.F.); (C.S.H.); (J.I.); (K.P.)
- Adelaide School of Medicine and the Robinson Research Institute, University of Adelaide, Adelaide, SA 5005, Australia
- School of Biological Sciences, University of Adelaide, Adelaide, SA 5005, Australia
| | - Holger Garn
- Translational Inflammation Research Division & Core Facility for Single Cell Multiomics, Medical Faculty, Philipps University Marburg, Member of the German Center for Lung Research (DZL) and the Universities of Giessen and Marburg Lung Center, 35043 Marburg, Germany; (H.G.); (S.M.)
| | - Johan Garssen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands;
- Danone Nutricia Research, 3584 CT Utrecht, The Netherlands
| | - Charles S. Hii
- Department of Immunopathology, SA Pathology at the Women’s and Children’s Hospital, North Adelaide, SA 5006, Australia; (A.F.); (C.S.H.); (J.I.); (K.P.)
- Adelaide School of Medicine and the Robinson Research Institute, University of Adelaide, Adelaide, SA 5005, Australia
| | - James Irvine
- Department of Immunopathology, SA Pathology at the Women’s and Children’s Hospital, North Adelaide, SA 5006, Australia; (A.F.); (C.S.H.); (J.I.); (K.P.)
- Adelaide School of Medicine and the Robinson Research Institute, University of Adelaide, Adelaide, SA 5005, Australia
| | - Kevin Llinás-Caballero
- Institute for Immunological Research, University of Cartagena, Cartagena 130014, Colombia; (N.A.); (L.C.); (K.L.-C.); (J.F.L.)
| | - Juan Felipe López
- Institute for Immunological Research, University of Cartagena, Cartagena 130014, Colombia; (N.A.); (L.C.); (K.L.-C.); (J.F.L.)
| | - Sarah Miethe
- Translational Inflammation Research Division & Core Facility for Single Cell Multiomics, Medical Faculty, Philipps University Marburg, Member of the German Center for Lung Research (DZL) and the Universities of Giessen and Marburg Lung Center, 35043 Marburg, Germany; (H.G.); (S.M.)
| | - Khalida Perveen
- Department of Immunopathology, SA Pathology at the Women’s and Children’s Hospital, North Adelaide, SA 5006, Australia; (A.F.); (C.S.H.); (J.I.); (K.P.)
- Adelaide School of Medicine and the Robinson Research Institute, University of Adelaide, Adelaide, SA 5005, Australia
| | - Elke Pogge von Strandmann
- Institute of Tumor Immunology, Clinic for Hematology, Oncology and Immunology, Center for Tumor Biology and Immunology, Philipps University Marburg, 35043 Marburg, Germany; (B.A.A.); (E.P.v.S.)
| | - Milena Sokolowska
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, 7265 Davos, Switzerland; (M.D.); (M.S.)
- Christine Kühne-Center for Allergy Research and Education, 7265 Davos, Switzerland
| | - Daniel P. Potaczek
- Translational Inflammation Research Division & Core Facility for Single Cell Multiomics, Medical Faculty, Philipps University Marburg, Member of the German Center for Lung Research (DZL) and the Universities of Giessen and Marburg Lung Center, 35043 Marburg, Germany; (H.G.); (S.M.)
| | - Betty C. A. M. van Esch
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands;
- Danone Nutricia Research, 3584 CT Utrecht, The Netherlands
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Niu F, Sharma A, Wang Z, Feng L, Muresanu DF, Sahib S, Tian ZR, Lafuente JV, Buzoianu AD, Castellani RJ, Nozari A, Patnaik R, Wiklund L, Sharma HS. Co-administration of TiO 2-nanowired dl-3-n-butylphthalide (dl-NBP) and mesenchymal stem cells enhanced neuroprotection in Parkinson's disease exacerbated by concussive head injury. PROGRESS IN BRAIN RESEARCH 2020; 258:101-155. [PMID: 33223034 DOI: 10.1016/bs.pbr.2020.09.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
dl-3-n-butylphthalide (dl-NBP) is a powerful antioxidant compound with profound neuroprotective effects in stroke and brain injury. However, its role in Parkinson's disease (PD) is not well known. Traumatic brain injury (TBI) is one of the key factors in precipitating PD like symptoms in civilians and particularly in military personnel. Thus, it would be interesting to explore the possible neuroprotective effects of NBP in PD following concussive head injury (CHI). In this chapter effect of nanowired delivery of NBP together with mesenchymal stem cells (MSCs) in PD with CHI is discussed based on our own investigations. It appears that CHI exacerbates PD pathophysiology in terms of p-tau, α-synuclein (ASNC) levels in the cerebrospinal fluid (CSF) and the loss of TH immunoreactivity in substantia niagra pars compacta (SNpc) and striatum (STr) along with dopamine (DA), dopamine decarboxylase (DOPAC). And homovanillic acid (HVA). Our observations are the first to show that a combination of NBP with MSCs when delivered using nanowired technology induces superior neuroprotective effects in PD brain pathology exacerbated by CHI, not reported earlier.
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Affiliation(s)
- Feng Niu
- CSPC NBP Pharmaceutical Medicine, Shijiazhuang, Hebei Province, China
| | - Aruna Sharma
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden.
| | - Zhenguo Wang
- CSPC NBP Pharmaceutical Medicine, Shijiazhuang, Hebei Province, China
| | - Lianyuan Feng
- Department of Neurology, Bethune International Peace Hospital, Shijiazhuang, Hebei Province, China
| | - Dafin F Muresanu
- Department of Clinical Neurosciences, University of Medicine & Pharmacy, Cluj-Napoca, Romania; "RoNeuro" Institute for Neurological Research and Diagnostic, Cluj-Napoca, Romania
| | - Seaab Sahib
- Department of Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, United States
| | - Z Ryan Tian
- Department of Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, United States
| | - José Vicente Lafuente
- LaNCE, Department of Neuroscience, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain
| | - Anca D Buzoianu
- Department of Clinical Pharmacology and Toxicology, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Rudy J Castellani
- Department of Pathology, University of Maryland, Baltimore, MD, United States
| | - Ala Nozari
- Anesthesiology & Intensive Care, Massachusetts General Hospital, Boston, MA, United States
| | - Ranjana Patnaik
- Department of Biomaterials, School of Biomedical Engineering, Indian Institute of Technology, Banaras Hindu University, Varanasi, India
| | - Lars Wiklund
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden
| | - Hari Shanker Sharma
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden.
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Sanyal T, Paul M, Bhattacharjee S, Bhattacharjee P. Epigenetic alteration of mitochondrial biogenesis regulatory genes in arsenic exposed individuals (with and without skin lesions) and in skin cancer tissues: A case control study. CHEMOSPHERE 2020; 258:127305. [PMID: 32563914 DOI: 10.1016/j.chemosphere.2020.127305] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 05/28/2020] [Accepted: 06/01/2020] [Indexed: 05/22/2023]
Abstract
Chronic arsenic toxicity has become a global concern due to its adverse pathophysiological outcome and carcinogenic potential. It is already established that arsenic induced reactive oxygen species alters mitochondrial functionality. Major regulatory genes for mitochondrial biogenesis, i.e., PGC1α, Tfam, NRF1and NRF2 are located in the nucleus. As a result, mitochondria-nucleus crosstalk is crucial for proper mitochondrial function. This previous hypothesis led us to investigateinvolvement of epigenetic alteration behindenhanced mitochondrial biogenesis in chronic arsenic exposure. An extensive case-control study was conducted with 390 study participants (unexposed, exposed without skin lesion, exposed with skin lesion and exposed skin tumour) from highly arsenic exposed areas ofWest Bengal, India. Methylation specific PCRrevealed significant promoter hypomethylation oftwo key biogenesis regulatory genes, PGC1αandTfam in arsenic exposed individuals and also in skin tumour tissues. Linear regression analysis indicated significant negative correlation between urinary arsenic concentration and promoter methylation status. Increased expression of biogenesis regulatory genes wasobtained by quantitative real-time PCR analysis. Moreover, altered mitochondrial fusion-fission regulatory gene expression was also observed in skin tumour tissues. miR663, having tumour suppressor gene like function was known to be epigenetically regulated through mitochondrial retrograde signal. Promoter hypermethylation with significantly decreased expression of miR663 was found in skin cancer tissues compared to non-cancerous control tissue. In conclusion, results indicated crucial role of epigenetic alteration in arsenic induced mitochondrial biogenesis and arsenical skin carcinogenesis for the first time. However, further mechanistic studies are necessary for detailed understanding of mitochondria-nucleus crosstalk in arsenic perturbation.
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Affiliation(s)
- Tamalika Sanyal
- Department of Zoology, University of Calcutta, Kolkata, 700019, India; Department of Environmental Science, University of Calcutta, Kolkata, 700019, India
| | - Manabi Paul
- Department of Environmental Science, University of Calcutta, Kolkata, 700019, India
| | | | - Pritha Bhattacharjee
- Department of Environmental Science, University of Calcutta, Kolkata, 700019, India.
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Zhang Q, Wu Y, Xu Q, Ma F, Zhang CY. Recent advances in biosensors for in vitro detection and in vivo imaging of DNA methylation. Biosens Bioelectron 2020; 171:112712. [PMID: 33045657 DOI: 10.1016/j.bios.2020.112712] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/25/2020] [Accepted: 10/07/2020] [Indexed: 02/08/2023]
Abstract
DNA methylation is the predominant epigenetic modification that participates in many fundamental cellular processes through posttranscriptional regulation of gene expression. Aberrant DNA methylation is closely associated with a variety of human diseases including cancers. Therefore, accurate and sensitive detection of DNA methylation may greatly facilitate the epigenetic biological researches and disease diagnosis. In recent years, a series of novel biosensors have been developed for highly sensitive detection of DNA methylation, but an overview of recent advances in biosensors for in vitro detection and especially live-cell imaging of DNA methylation is absent. In this review, we summarize the emerging biosensors for in vitro and in vivo DNA methylation assays in the past five years (2015-2020). Based on the signal types, the biosensors for in vitro DNA methylation assay are classified into five categories including fluorescent, electrochemical, colorimetric, surface enhanced Raman spectroscopy, mass spectrometry, and surface plasmon resonance biosensors, while the biosensors for in vivo DNA methylation assay mainly rely on fluorescent imaging. We review the strategies, features and applications of these biosensors, and provide a new insight into the challenges and future directions in this area.
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Affiliation(s)
- Qian Zhang
- College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Shandong Provincial Key Laboratory of Clean Production of Fine Chemicals, Shandong Normal University, Jinan, 250014, China
| | - Yanxia Wu
- Department of Pathology and Pathological Diagnosis & Research Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Qinfeng Xu
- School of Food and Biological Engineering, National R&D Center for Goat Dairy Products Processing Technology, Shaanxi University of Science and Technology, Xi'an, 710021, China
| | - Fei Ma
- College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Shandong Provincial Key Laboratory of Clean Production of Fine Chemicals, Shandong Normal University, Jinan, 250014, China.
| | - Chun-Yang Zhang
- College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Shandong Provincial Key Laboratory of Clean Production of Fine Chemicals, Shandong Normal University, Jinan, 250014, China.
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50
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Mitochondrial biogenesis in organismal senescence and neurodegeneration. Mech Ageing Dev 2020; 191:111345. [DOI: 10.1016/j.mad.2020.111345] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 08/17/2020] [Accepted: 08/27/2020] [Indexed: 12/19/2022]
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