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Kumar D, Kumar R, Janrao S, Sharma V, Begum N, Fernandes V, Khatri DK. Treadmill exercise mitigates rotenone-induced neuroinflammation and α-synuclein level in a mouse model of Parkinson's disease. Brain Res 2025; 1854:149540. [PMID: 40023234 DOI: 10.1016/j.brainres.2025.149540] [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: 11/15/2024] [Revised: 02/15/2025] [Accepted: 02/25/2025] [Indexed: 03/04/2025]
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting 7-10 million people globally. It presents with motor symptoms like bradykinesia, tremors, rigidity, and postural instability, along with non-motor issues such as anxiety and mood fluctuations. PD is characterized by the progressive loss of nigrostriatal neurons, α-synuclein protein aggregation, reduced tyrosine hydroxylase level, and impaired dopamine signaling. Neuroinflammation plays a key role in PD progression, with elevated pro-inflammatory cytokines promoting M1 microglial activation, which exacerbates neurodegeneration. Conversely, anti-inflammatory cytokines such as IL-10 and IL-4 help shift microglia to the neuroprotective M2 phenotype, reducing inflammation. Animal models show an imbalance with increased M1 and reduced M2 microglia. This study explored the neuroprotective effects of treadmill exercise in a rotenone-induced PD mouse model. After 21 days of exercise, behavioral impairments improved, as shown by open field tests, Rota-rod, and footprint analysis. Exercise also reduced pro-inflammatory cytokines; TNF-α, and IL-1β levels while increasing anti-inflammatory cytokines; IL-10, and IL-4. This shift correlated with decreased α-synuclein levels and increased tyrosine hydroxylase expression, indicating reduced neurodegeneration. These findings suggest that treadmill exercise can mitigate PD symptoms and pathology by modulating neuroinflammation and restoring dopaminergic function.
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Affiliation(s)
- Deepak Kumar
- Department of Biologicals Science, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Rohith Kumar
- Department of Biologicals Science, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Sushmita Janrao
- Department of Biologicals Science, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Vaishnavi Sharma
- Department of Biologicals Science, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Nusrat Begum
- Department of Biologicals Science, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Valencia Fernandes
- Department of Biologicals Science, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Dharmendra Kumar Khatri
- Department of Pharmacology, NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, India.
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2
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Gao Y, Chen Y, Wang N, Meng Q. Albiflorin ameliorates neuroinflammation and exerts neuroprotective effects in Parkinson's disease models. Immunopharmacol Immunotoxicol 2025; 47:201-212. [PMID: 39924948 DOI: 10.1080/08923973.2025.2457960] [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: 03/25/2024] [Accepted: 01/18/2025] [Indexed: 02/11/2025]
Abstract
BACKGROUND Albiflorin isolated from Paeoniae Alba Radix can cross the blood-brain barrier (BBB) and possesses analgesia, anticonvulsant, anti-inflammatory, and hepatoprotective properties. This study investigates albiflorin functions and related mechanisms in Parkinson's disease (PD) pathogenesis. METHODS Cellular and animal models of PD were constructed. Cell viability and apoptosis were detected by CCK-8 assays. Levels of Iba-1 and TH were measured by immunofluorescence staining, western blotting, and immunohistochemistry staining. Levels of pro-inflammatory mediators and pathway-related genes were measured by western blotting and RT-qPCR. Locomotor activity of mice was examined by open field test, rod climbing test, and rod rotating test. RESULTS For in vitro analysis, albiflorin inhibited LPS-induced microglial activation and neuroinflammation. Additionally, albiflorin inactivated NF-κB and MAPK pathways in LPS-treated BV2 cells. Moreover, albiflorin attenuated neurotoxicity mediated by LPS-stimulated microglia. For in vivo analysis, albiflorin improved MPTP-induced locomotor activity deficits and reduced MPTP-induced dopaminergic neuron loss. In parallel, albiflorin inhibited activated microglia-mediated neuroinflammation in MPTP-treated mice. CONCLUSION Albiflorin mitigates neuronal apoptosis and improves behavioral impairments in MPTP-induced PD mouse model through inhibition of activated microglia-mediated neuroinflammation via the NF-κB and MAPK pathways.
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Affiliation(s)
- Yuan Gao
- Department of Neurology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
- Medical School, Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Yanmei Chen
- Medical School, Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Ning Wang
- Medical School, Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Qiang Meng
- Department of Neurology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
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3
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Eslami M, Raji-Amirhasani A, Khaksari M, Keshavarzi Z, Rostamzadeh F, Sabet N, Jafari E, Soltani Z, Karamouzian S. The changes of digestive system inflammatory, oxidative stress, and histopathology factors following oral mesenchymal stem cells administration in rats with traumatic brain injury. BMC Neurosci 2025; 26:20. [PMID: 40050727 PMCID: PMC11884162 DOI: 10.1186/s12868-025-00936-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 02/10/2025] [Indexed: 03/10/2025] Open
Abstract
BACKGROUND AND AIMS Mucous mesenchymal stem cells can migrate to damaged areas, and their use is proposed as a new approach to treating diseases. The present study aimed to investigate the effect of oral mesenchymal stem cells (OMSCs) on inflammatory, oxidative stress, and histopathological indices in the tissues of the stomach, intestine, and colon after traumatic brain injury (TBI). METHODS AND MATERIALS Adult male rats were randomly divided into four groups: Sham, TBI, Vehicle (Veh), and Stem cell (SC). Intravenous injection of OMSCs was performed at 1 and 24 h after injury. The inflammatory, oxidative stress, and histopathological indices of the tissues of the stomach, small intestine, and colon were evaluated 48 h after injury. RESULTS After TBI, IL-1β and IL-6 levels increased and IL-10 levels decreased in the tissues of the stomach, small intestine, and colon, but the administration of OMSCS prevented these changes to a large extent. Oxidative stress indices (MDA, PC, TAC, SOD, and CAT) showed an increase in oxidative stress after TBI, but oxidative stress was less severe in the OMSC group. The administration of OMSCs after TBI improved the histopathological outcome in the tissues of the stomach, small intestine, and colon. CONCLUSION Administration of OMSCs in rats suffering from TBI can improve inflammatory, oxidative stress, and histopathological indices in the tissues of the stomach, small intestine, and colon, which shows the beneficial effect of using OMSCs in TBI.
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Affiliation(s)
- Masoud Eslami
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Alireza Raji-Amirhasani
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammad Khaksari
- Endocrinology and Metabolism Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Zakieh Keshavarzi
- Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Farzaneh Rostamzadeh
- Cardiovascular Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Nazanin Sabet
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Elham Jafari
- Pathology and Stem Cells Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Zahra Soltani
- Endocrinology and Metabolism Research Center, Kerman University of Medical Sciences, Kerman, Iran.
| | - Saeed Karamouzian
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
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4
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DeFranco JP, Telling GC. The Evolution of Experimental Rodent Models for Prion Diseases. J Neurochem 2025; 169:e70039. [PMID: 40108932 PMCID: PMC11968085 DOI: 10.1111/jnc.70039] [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: 12/17/2024] [Revised: 02/01/2025] [Accepted: 02/24/2025] [Indexed: 03/22/2025]
Abstract
Prion diseases are a group of fatal, neurodegenerative diseases that affect animals and humans. These diseases are characterized by the conformational conversion of normal, host-encoded PrPC into a disease-causing prion isoform, PrPSc. Significant advancements in biological, genetic, and prion research have led to the capability of studying this pathogenetic process using recombinant proteins, ex vivo systems, in vitro models, and mammalian hosts, the latter being the gold standard for assaying prion infectivity, transmission, and strain evolution. While devoid of nucleic acid, prions encipher strain information by the conformation of their constituent infectious proteins, with diversity altering pathogenesis, host-range dynamics, and the efficacy of therapeutics. To properly study the strain properties of natural prions and develop appropriate therapeutic strategies, it is essential to utilize models that authentically recapitulate these infectious agents in experimental mammalian hosts. In this review, we examine the evolution of research on prion diseases using non-transgenic and transgenic animals, primarily focusing on rodent models. We discuss the successes and limitations of each experimental system and provide insights based on recent findings in novel gene-targeted mice.
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Affiliation(s)
- Joseph P. DeFranco
- Prion Research Center, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado, USA
| | - Glenn C. Telling
- Prion Research Center, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado, USA
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5
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Lamichhane S, Seo JE, Jeong JH, Lee S, Lee S. Ideal animal models according to multifaceted mechanisms and peculiarities in neurological disorders: present and challenges. Arch Pharm Res 2025; 48:62-88. [PMID: 39690343 DOI: 10.1007/s12272-024-01527-9] [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: 09/04/2024] [Accepted: 12/04/2024] [Indexed: 12/19/2024]
Abstract
Neurological disorders, encompassing conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), pose a significant global health challenge, affecting millions worldwide. With an aging population and increased life expectancy, the prevalence of these disorders is escalating rapidly, leading to substantial economic burdens exceeding trillions of dollars annually. Animal models play a crucial role in understanding the underlying mechanisms of these disorders and developing effective treatments. Various species, including rodents, non-human primates, and fruit flies, are utilized to replicate specific aspects of human neurological conditions. However, selecting the ideal animal model requires careful consideration of its proximity to human disease conditions and its ability to mimic disease pathobiology and pharmacological responses. An Animal Model Quality Assessment (AMQA) tool has been developed to facilitate this selection process, focusing on assessing models based on their similarity to human conditions and disease pathobiology. Therefore, integrating intrinsic and extrinsic factors linked to the disease into the study's objectives aids in constructing a biological information matrix for comparing disease progression between the animal model and human disease. Ultimately, selecting an ideal animal disease model depends on its predictive, face, and construct validity, ensuring relevance and reliability in translational research efforts.
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Affiliation(s)
- Shrawani Lamichhane
- College of Pharmacy, Chung-Ang University, 84 Heukseok-Ro, Dongjak-Gu, Seoul, 06974, Republic of Korea
| | - Jo-Eun Seo
- College of Pharmacy, Chung-Ang University, 84 Heukseok-Ro, Dongjak-Gu, Seoul, 06974, Republic of Korea
| | - Ji Hoon Jeong
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Sooyeun Lee
- College of Pharmacy, Keimyung University, Daegu, 42601, Republic of Korea
| | - Sangkil Lee
- College of Pharmacy, Chung-Ang University, 84 Heukseok-Ro, Dongjak-Gu, Seoul, 06974, Republic of Korea.
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Barmpa K, Saraiva C, Lopez-Pigozzi D, Gomez-Giro G, Gabassi E, Spitz S, Brandauer K, Rodriguez Gatica JE, Antony P, Robertson G, Sabahi-Kaviani R, Bellapianta A, Papastefanaki F, Luttge R, Kubitscheck U, Salti A, Ertl P, Bortolozzi M, Matsas R, Edenhofer F, Schwamborn JC. Modeling early phenotypes of Parkinson's disease by age-induced midbrain-striatum assembloids. Commun Biol 2024; 7:1561. [PMID: 39580573 PMCID: PMC11585662 DOI: 10.1038/s42003-024-07273-4] [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: 06/20/2024] [Accepted: 11/14/2024] [Indexed: 11/25/2024] Open
Abstract
Parkinson's disease, an aging-associated neurodegenerative disorder, is characterised by nigrostriatal pathway dysfunction caused by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain. Human in vitro models are enabling the study of the dopaminergic neurons' loss, but not the dysregulation within the dopaminergic network in the nigrostriatal pathway. Additionally, these models do not incorporate aging characteristics which potentially contribute to the development of Parkinson's disease. Here we present a nigrostriatal pathway model based on midbrain-striatum assembloids with inducible aging. We show that these assembloids can develop characteristics of the nigrostriatal connectivity, with catecholamine release from the midbrain to the striatum and synapse formation between midbrain and striatal neurons. Moreover, Progerin-overexpressing assembloids acquire aging traits that lead to early neurodegenerative phenotypes. This model shall help to reveal the contribution of aging as well as nigrostriatal connectivity to the onset and progression of Parkinson's disease.
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Affiliation(s)
- Kyriaki Barmpa
- Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Claudia Saraiva
- Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Diego Lopez-Pigozzi
- Department of Physics and Astronomy "G. Galilei", University of Padua, Padua, Italy
- Veneto Institute of Molecular Medicine (VIMM), Padua, Italy
| | - Gemma Gomez-Giro
- Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Elisa Gabassi
- Genomics, Stem Cell & Regenerative Medicine Group and CMBI, Institute of Molecular Biology, University of Innsbruck, Innsbruck, Austria
| | - Sarah Spitz
- Institute of Applied Synthetic Chemistry, Vienna University of Technology, Vienna, Austria
| | - Konstanze Brandauer
- Institute of Applied Synthetic Chemistry, Vienna University of Technology, Vienna, Austria
| | | | - Paul Antony
- Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Graham Robertson
- Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | | | - Alessandro Bellapianta
- Johannes Kepler University Linz, Kepler University Hospital, University Clinic for Ophthalmology and Optometry, Linz, Austria
| | - Florentia Papastefanaki
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur Institute, Athens, Greece
- Human Embryonic and Induced Pluripotent Stem Cell Unit, Hellenic Pasteur Institute, Athens, Greece
| | - Regina Luttge
- Eindhoven University of Technology, Microsystems, Eindhoven, Netherlands
| | - Ulrich Kubitscheck
- Clausius Institute of Physical and Theoretical Chemistry, University of Bonn, Bonn, Germany
| | - Ahmad Salti
- Genomics, Stem Cell & Regenerative Medicine Group and CMBI, Institute of Molecular Biology, University of Innsbruck, Innsbruck, Austria
- Johannes Kepler University Linz, Kepler University Hospital, University Clinic for Ophthalmology and Optometry, Linz, Austria
| | - Peter Ertl
- Institute of Applied Synthetic Chemistry, Vienna University of Technology, Vienna, Austria
| | - Mario Bortolozzi
- Department of Physics and Astronomy "G. Galilei", University of Padua, Padua, Italy
- Veneto Institute of Molecular Medicine (VIMM), Padua, Italy
| | - Rebecca Matsas
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur Institute, Athens, Greece
- Human Embryonic and Induced Pluripotent Stem Cell Unit, Hellenic Pasteur Institute, Athens, Greece
| | - Frank Edenhofer
- Genomics, Stem Cell & Regenerative Medicine Group and CMBI, Institute of Molecular Biology, University of Innsbruck, Innsbruck, Austria
| | - Jens C Schwamborn
- Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
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Chen J, Volkmann J, Ip CW. A framework for translational therapy development in deep brain stimulation. NPJ Parkinsons Dis 2024; 10:216. [PMID: 39516465 PMCID: PMC11549317 DOI: 10.1038/s41531-024-00829-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 10/23/2024] [Indexed: 11/16/2024] Open
Abstract
Deep brain stimulation (DBS) is an established treatment for motor disorders like Parkinson's disease, but its mechanisms and effects on neurons and networks are not fully understood, limiting research-driven progress. This review presents a framework that combines neurophysiological insights and translational research to enhance DBS therapy, emphasizing biomarkers, device technology, and symptom-specific neuromodulation. It also examines the role of animal research in improving DBS, while acknowledging challenges in clinical translation.
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Affiliation(s)
- Jiazhi Chen
- Department of Neurology, University Hospital of Würzburg, Josef-Schneider-Straße 11, Würzburg, Germany
| | - Jens Volkmann
- Department of Neurology, University Hospital of Würzburg, Josef-Schneider-Straße 11, Würzburg, Germany
| | - Chi Wang Ip
- Department of Neurology, University Hospital of Würzburg, Josef-Schneider-Straße 11, Würzburg, Germany.
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8
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Currie AD, Wong JK, Okun MS. A review of temporal interference, nanoparticles, ultrasound, gene therapy, and designer receptors for Parkinson disease. NPJ Parkinsons Dis 2024; 10:195. [PMID: 39443513 PMCID: PMC11500395 DOI: 10.1038/s41531-024-00804-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Accepted: 09/25/2024] [Indexed: 10/25/2024] Open
Abstract
In this review, we summarize preclinical and clinical trials investigating innovative neuromodulatory approaches for Parkinson disease (PD) motor symptom management. We highlight the following technologies: temporal interference, nanoparticles for drug delivery, blood-brain barrier opening, gene therapy, optogenetics, upconversion nanoparticles, magnetothermal nanoparticles, magnetoelectric nanoparticles, ultrasound-responsive nanoparticles, and designer receptors exclusively activated by designer drugs. These studies establish the basis for novel and promising neuromodulatory treatments for PD motor symptoms.
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Affiliation(s)
- A D Currie
- Department of Neurology, Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, USA.
| | - J K Wong
- Department of Neurology, Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, USA
| | - M S Okun
- Department of Neurology, Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, USA
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Cho Y, Seo EU, Hwang KS, Kim H, Choi J, Kim HN. Evaluation of size-dependent uptake, transport and cytotoxicity of polystyrene microplastic in a blood-brain barrier (BBB) model. NANO CONVERGENCE 2024; 11:40. [PMID: 39406944 PMCID: PMC11480280 DOI: 10.1186/s40580-024-00448-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 10/01/2024] [Indexed: 10/19/2024]
Abstract
Microplastics, particularly those in the micrometer scale, have been shown to enter the human body through ingestion, inhalation, and dermal contact. Recent research indicates that microplastics can potentially impact the central nervous system (CNS) by crossing the blood-brain barrier (BBB). However, the exact mechanisms of their transport, uptake, and subsequent toxicity at BBB remain unclear. In this study, we evaluated the size-dependent uptake and cytotoxicity of polystyrene microparticles using an engineered BBB model. Our findings demonstrate that 0.2 μm polystyrene microparticles exhibit significantly higher uptake and transendothelial transport compared to 1.0 μm polystyrene microparticles, leading to increased permeability and cellular damage. After 24 h of exposure, permeability increased by 15.6-fold for the 0.2 μm particles and 2-fold for the 1.0 μm particles compared to the control. After 72 h of exposure, permeability further increased by 27.3-fold for the 0.2 μm particles and a 4.5-fold for the 1.0 μm particles compared to the control. Notably, microplastics administration following TNF-α treatment resulted in enhanced absorption and greater BBB damage compared to non-stimulated conditions. Additionally, the size-dependent toxicity observed differently between 2D cultured cells and 3D BBB models, highlighting the importance of testing models in evaluating environmental toxicity.
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Affiliation(s)
- Yeongseon Cho
- Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea
- School of Integrative Engineering, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Eun U Seo
- Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea
- Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology (UST), Seoul, 02792, Republic of Korea
| | - Kyeong Seob Hwang
- Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea
| | - Hyelim Kim
- Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea
- Department of Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea
| | - Jonghoon Choi
- School of Integrative Engineering, Chung-Ang University, Seoul, 06974, Republic of Korea.
| | - Hong Nam Kim
- Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea.
- Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology (UST), Seoul, 02792, Republic of Korea.
- University of Science and Technology, Seoul, 02792, Republic of Korea.
- School of Mechanical Engineering, Yonsei University, Seoul, 03722, Republic of Korea.
- Yonsei-Korea Institute of Science and Technology Convergence Research Institute, Yonsei University, Seoul, 03722, Republic of Korea.
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Goldman C, Kareva T, Sarrafha L, Schuldt BR, Sahasrabudhe A, Ahfeldt T, Blanchard JW. Genetically Encoded and Modular SubCellular Organelle Probes (GEM-SCOPe) reveal lysosomal and mitochondrial dysfunction driven by PRKN knockout. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.21.594886. [PMID: 38979135 PMCID: PMC11230217 DOI: 10.1101/2024.05.21.594886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 07/10/2024]
Abstract
Cellular processes including lysosomal and mitochondrial dysfunction are implicated in the development of many diseases. Quantitative visualization of mitochondria and lysosoesl is crucial to understand how these organelles are dysregulated during disease. To address a gap in live-imaging tools, we developed GEM-SCOPe (Genetically Encoded and Modular SubCellular Organelle Probes), a modular toolbox of fluorescent markers designed to inform on localization, distribution, turnover, and oxidative stress of specific organelles. We expressed GEM-SCOPe in differentiated astrocytes and neurons from a human pluripotent stem cell PRKN-knockout model of Parkinson's disease and identified disease-associated changes in proliferation, lysosomal distribution, mitochondrial transport and turnover, and reactive oxygen species. We demonstrate GEM-SCOPe is a powerful panel that provide critical insight into the subcellular mechanisms underlying Parkinson's disease in human cells. GEM-SCOPe can be expanded upon and applied to a diversity of cellular models to glean an understanding of the mechanisms that promote disease onset and progression.
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Affiliation(s)
- Camille Goldman
- Icahn School of Medicine, Mount Sinai, New York, NY, USA
- Nash Family Department of Neuroscience, Mount Sinai, New York, NY, USA
- Friedman Brain Institute, Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer’s Disease, Mount Sinai, New York, NY USA
- Black Family Stem Cell Institute, Mount Sinai, New York, NY, USA
| | - Tatyana Kareva
- Icahn School of Medicine, Mount Sinai, New York, NY, USA
- Nash Family Department of Neuroscience, Mount Sinai, New York, NY, USA
- Friedman Brain Institute, Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer’s Disease, Mount Sinai, New York, NY USA
- Black Family Stem Cell Institute, Mount Sinai, New York, NY, USA
| | - Lily Sarrafha
- Icahn School of Medicine, Mount Sinai, New York, NY, USA
- Nash Family Department of Neuroscience, Mount Sinai, New York, NY, USA
- Friedman Brain Institute, Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer’s Disease, Mount Sinai, New York, NY USA
- Black Family Stem Cell Institute, Mount Sinai, New York, NY, USA
| | - Braxton R. Schuldt
- Icahn School of Medicine, Mount Sinai, New York, NY, USA
- Nash Family Department of Neuroscience, Mount Sinai, New York, NY, USA
- Friedman Brain Institute, Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer’s Disease, Mount Sinai, New York, NY USA
- Black Family Stem Cell Institute, Mount Sinai, New York, NY, USA
| | - Abhishek Sahasrabudhe
- Icahn School of Medicine, Mount Sinai, New York, NY, USA
- Nash Family Department of Neuroscience, Mount Sinai, New York, NY, USA
- Friedman Brain Institute, Mount Sinai, New York, NY, USA
| | - Tim Ahfeldt
- Icahn School of Medicine, Mount Sinai, New York, NY, USA
- Nash Family Department of Neuroscience, Mount Sinai, New York, NY, USA
- Friedman Brain Institute, Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer’s Disease, Mount Sinai, New York, NY USA
- Black Family Stem Cell Institute, Mount Sinai, New York, NY, USA
| | - Joel W. Blanchard
- Icahn School of Medicine, Mount Sinai, New York, NY, USA
- Nash Family Department of Neuroscience, Mount Sinai, New York, NY, USA
- Friedman Brain Institute, Mount Sinai, New York, NY, USA
- Ronald M. Loeb Center for Alzheimer’s Disease, Mount Sinai, New York, NY USA
- Black Family Stem Cell Institute, Mount Sinai, New York, NY, USA
- Lead Contact
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Dautan D, Paslawski W, Montejo SG, Doyon DC, Marangiu R, Kaplitt MG, Chen R, Dawson VL, Zhang X, Dawson TM, Svenningsson P. Gut-Initiated Alpha Synuclein Fibrils Drive Parkinson's Disease Phenotypes: Temporal Mapping of non-Motor Symptoms and REM Sleep Behavior Disorder. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.22.590542. [PMID: 38712208 PMCID: PMC11071367 DOI: 10.1101/2024.04.22.590542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2024]
Abstract
Parkinson's disease (PD) is characterized by progressive motor as well as less recognized non-motor symptoms that arise often years before motor manifestation, including sleep and gastrointestinal disturbances. Despite the heavy burden on the patient's quality of life, these non-motor manifestations are poorly understood. To elucidate the temporal dynamics of the disease, we employed a mouse model involving injection of alpha-synuclein (αSyn) pre-formed fibrils (PFF) in the duodenum and antrum as a gut-brain model of Parkinsonism. Using anatomical mapping of αSyn-PFF propagation and behavioral and physiological characterizations, we unveil a correlation between post-injection time the temporal dynamics of αSyn propagation and non-motor/motor manifestations of the disease. We highlight the concurrent presence of αSyn aggregates in key brain regions, expressing acetylcholine or dopamine, involved in sleep duration, wakefulness, and particularly REM-associated atonia corresponding to REM behavioral disorder-like symptoms. This study presents a novel and in-depth exploration into the multifaceted nature of PD, unraveling the complex connections between α-synucleinopathies, gut-brain connectivity, and the emergence of non-motor phenotypes.
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Affiliation(s)
- Daniel Dautan
- Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden
- Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA
| | - Wojciech Paslawski
- Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden
- Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA
| | - Sergio G. Montejo
- Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden
| | - Daniel C. Doyon
- Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden
| | - Roberta Marangiu
- Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA
- Division of Neurosurgery, Department of Neurosurgery, New-York Hospital-Cornell Medical College, New York, NY, USA
| | - Michael G. Kaplitt
- Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA
- Division of Neurosurgery, Department of Neurosurgery, New-York Hospital-Cornell Medical College, New York, NY, USA
| | - Rong Chen
- Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Valina L. Dawson
- Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
- Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Xiaoaun Zhang
- Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden
| | - Ted M. Dawson
- Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Per Svenningsson
- Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden
- Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA
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12
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Cavallo A, Neumann WJ. Dopaminergic reinforcement in the motor system: Implications for Parkinson's disease and deep brain stimulation. Eur J Neurosci 2024; 59:457-472. [PMID: 38178558 DOI: 10.1111/ejn.16222] [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: 09/19/2023] [Revised: 11/16/2023] [Accepted: 11/17/2023] [Indexed: 01/06/2024]
Abstract
Millions of people suffer from dopamine-related disorders spanning disturbances in movement, cognition and emotion. These changes are often attributed to changes in striatal dopamine function. Thus, understanding how dopamine signalling in the striatum and basal ganglia shapes human behaviour is fundamental to advancing the treatment of affected patients. Dopaminergic neurons innervate large-scale brain networks, and accordingly, many different roles for dopamine signals have been proposed, such as invigoration of movement and tracking of reward contingencies. The canonical circuit architecture of cortico-striatal loops sparks the question, of whether dopamine signals in the basal ganglia serve an overarching computational principle. Such a holistic understanding of dopamine functioning could provide new insights into symptom generation in psychiatry to neurology. Here, we review the perspective that dopamine could bidirectionally control neural population dynamics, increasing or decreasing their strength and likelihood to reoccur in the future, a process previously termed neural reinforcement. We outline how the basal ganglia pathways could drive strengthening and weakening of circuit dynamics and discuss the implication of this hypothesis on the understanding of motor signs of Parkinson's disease (PD), the most frequent dopaminergic disorder. We propose that loss of dopamine in PD may lead to a pathological brain state where repetition of neural activity leads to weakening and instability, possibly explanatory for the fact that movement in PD deteriorates with repetition. Finally, we speculate on how therapeutic interventions such as deep brain stimulation may be able to reinstate reinforcement signals and thereby improve treatment strategies for PD in the future.
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Affiliation(s)
- Alessia Cavallo
- Movement Disorder and Neuromodulation Unit, Department of Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Wolf-Julian Neumann
- Movement Disorder and Neuromodulation Unit, Department of Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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13
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Reumann D, Krauditsch C, Novatchkova M, Sozzi E, Wong SN, Zabolocki M, Priouret M, Doleschall B, Ritzau-Reid KI, Piber M, Morassut I, Fieseler C, Fiorenzano A, Stevens MM, Zimmer M, Bardy C, Parmar M, Knoblich JA. In vitro modeling of the human dopaminergic system using spatially arranged ventral midbrain-striatum-cortex assembloids. Nat Methods 2023; 20:2034-2047. [PMID: 38052989 PMCID: PMC10703680 DOI: 10.1038/s41592-023-02080-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 10/10/2023] [Indexed: 12/07/2023]
Abstract
Ventral midbrain dopaminergic neurons project to the striatum as well as the cortex and are involved in movement control and reward-related cognition. In Parkinson's disease, nigrostriatal midbrain dopaminergic neurons degenerate and cause typical Parkinson's disease motor-related impairments, while the dysfunction of mesocorticolimbic midbrain dopaminergic neurons is implicated in addiction and neuropsychiatric disorders. Study of the development and selective neurodegeneration of the human dopaminergic system, however, has been limited due to the lack of an appropriate model and access to human material. Here, we have developed a human in vitro model that recapitulates key aspects of dopaminergic innervation of the striatum and cortex. These spatially arranged ventral midbrain-striatum-cortical organoids (MISCOs) can be used to study dopaminergic neuron maturation, innervation and function with implications for cell therapy and addiction research. We detail protocols for growing ventral midbrain, striatal and cortical organoids and describe how they fuse in a linear manner when placed in custom embedding molds. We report the formation of functional long-range dopaminergic connections to striatal and cortical tissues in MISCOs, and show that injected, ventral midbrain-patterned progenitors can mature and innervate the tissue. Using these assembloids, we examine dopaminergic circuit perturbations and show that chronic cocaine treatment causes long-lasting morphological, functional and transcriptional changes that persist upon drug withdrawal. Thus, our method opens new avenues to investigate human dopaminergic cell transplantation and circuitry reconstruction as well as the effect of drugs on the human dopaminergic system.
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Affiliation(s)
- Daniel Reumann
- Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, Vienna BioCenter, Vienna, Austria
- Vienna BioCenter, Doctoral School of the University of Vienna and Medical University of Vienna, Vienna, Austria
| | - Christian Krauditsch
- Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, Vienna BioCenter, Vienna, Austria
| | - Maria Novatchkova
- Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, Vienna BioCenter, Vienna, Austria
| | - Edoardo Sozzi
- Department of Experimental Medical Science, Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Sakurako Nagumo Wong
- Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, Vienna BioCenter, Vienna, Austria
- Vienna BioCenter, Doctoral School of the University of Vienna and Medical University of Vienna, Vienna, Austria
| | - Michael Zabolocki
- Laboratory for Human Neurophysiology and Genetics, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia
- Flinders Health and Medical Research Institute, Flinders University, Adelaide, South Australia, Australia
| | - Marthe Priouret
- Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, Vienna BioCenter, Vienna, Austria
| | - Balint Doleschall
- Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, Vienna BioCenter, Vienna, Austria
- Vienna BioCenter, Doctoral School of the University of Vienna and Medical University of Vienna, Vienna, Austria
| | - Kaja I Ritzau-Reid
- Department of Materials, Department of Bioengineering, Institute of Biomedical Engineering, Imperial College London, London, UK
| | - Marielle Piber
- Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, Vienna BioCenter, Vienna, Austria
- Zebrafish Neurogenetics Unit, Institut Pasteur, Paris, France
| | - Ilaria Morassut
- Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, Vienna BioCenter, Vienna, Austria
- Department of Basic Neurosciences, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Charles Fieseler
- Department of Neuroscience and Developmental Biology, University of Vienna, Vienna, Austria
| | - Alessandro Fiorenzano
- Department of Experimental Medical Science, Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, Lund Stem Cell Center, Lund University, Lund, Sweden
- Stem Cell Fate Laboratory, Institute of Genetics and Biophysics 'Adriano Buzzati Traverso' (IGB), CNR, Naples, Italy
| | - Molly M Stevens
- Department of Materials, Department of Bioengineering, Institute of Biomedical Engineering, Imperial College London, London, UK
| | - Manuel Zimmer
- Department of Neuroscience and Developmental Biology, University of Vienna, Vienna, Austria
| | - Cedric Bardy
- Laboratory for Human Neurophysiology and Genetics, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia
- Flinders Health and Medical Research Institute, Flinders University, Adelaide, South Australia, Australia
| | - Malin Parmar
- Department of Experimental Medical Science, Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Jürgen A Knoblich
- Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, Vienna BioCenter, Vienna, Austria.
- Department of Neurology, Medical University of Vienna, Vienna, Austria.
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14
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Krzisch M, Yuan B, Chen W, Osaki T, Fu D, Garrett-Engele C, Svoboda D, Andrykovich K, Sur M, Jaenisch R. The A53T mutation in α-synuclein enhances pro-inflammatory activation in human microglia. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.29.555300. [PMID: 37693409 PMCID: PMC10491251 DOI: 10.1101/2023.08.29.555300] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/12/2023]
Abstract
Parkinson's disease (PD) is characterized by the aggregation of α-synuclein into Lewy bodies and Lewy neurites in the brain. Microglia-driven neuroinflammation may contribute to neuronal death in PD, however the exact role of microglia remains unclear and has been understudied. The A53T mutation in the gene coding for α-synuclein has been linked to early-onset PD, and exposure to A53T-mutant human α-synuclein increases the potential for inflammation of murine microglia. To date, its effect has not been studied in human microglia. Here, we used 2-dimensional cultures of human iPSC-derived microglia and transplantation of these cells into the mouse brain to assess the effects of the A53T mutation on human microglia. We found that A53T-mutant human microglia had an intrinsically increased propensity towards pro-inflammatory activation upon inflammatory stimulus. Additionally, A53T mutant microglia showed a strong decrease in catalase expression in non-inflammatory conditions, and increased oxidative stress. Our results indicate that A53T mutant human microglia display cell-autonomous phenotypes that may worsen neuronal damage in early-onset PD.
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15
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Andolfi A, Arnaldi P, Lisa DD, Pepe S, Frega M, Fassio A, Lagazzo A, Martinoia S, Pastorino L. A micropatterned thermoplasmonic substrate for neuromodulation of in vitro neuronal networks. Acta Biomater 2023; 158:281-291. [PMID: 36563774 DOI: 10.1016/j.actbio.2022.12.036] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 12/05/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022]
Abstract
Understanding how the spatial organization of a neural network affects its activity represents a leading issue in neuroscience. Thanks to their accessibility and easy handling, in vitro studies remain an essential tool to investigate the relationship between the structure and function of a neuronal network. Among all the patterning techniques, ink-jet printing acquired great interest thanks to its direct-write approach, which allows the patterned substrate realization without mold, leading to a considerable saving of both cost and time. However, the inks commonly used give the possibility to control only the structure of a neuronal network, leaving aside the functional aspect. In this work, we synthesize a photosensitive ink combining the rheological and bioadhesive properties of chitosan with the plasmonic properties of gold nanorods, obtaining an ink able to control both the spatial organization of a two-dimensional neuronal network and its activity through photothermal effect. After the ink characterization, we demonstrate that it is possible to print, with high precision, different geometries on a microelectrode array. In this way, it is possible obtaining a patterned device to control the structure of a neuronal network, to record its activity and to modulate it via photothermal effect. Finally, to our knowledge, we report the first evidence of photothermal inhibition of human neurons activity. STATEMENT OF SIGNIFICANCE: Patterned cell cultures remain the most efficient and simple tool for linking structural and functional studies, especially in the neuronal field. Ink-jet printing is the technique with which it is possible to realize patterned structures in the fastest, simple, versatile and low-cost way. However, the inks currently used permit the control only of the neuronal network structure but do not allow the control-modulation of the network activity. In this study, we realize and characterize a photosensitive bioink with which it is possible to drive both the structure and the activity of a neuronal network. Moreover, we report the first evidence of activity inhibition by the photothermal effect on human neurons as far as we know.
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Affiliation(s)
- Andrea Andolfi
- Department of Informatics, Bioengineering, Robotics and Systems Engineering (DIBRIS), University of Genoa, Genoa, Italy.
| | - Pietro Arnaldi
- Department of Informatics, Bioengineering, Robotics and Systems Engineering (DIBRIS), University of Genoa, Genoa, Italy.
| | - Donatella Di Lisa
- Department of Informatics, Bioengineering, Robotics and Systems Engineering (DIBRIS), University of Genoa, Genoa, Italy.
| | - Sara Pepe
- Department of Experimental Medicine, University of Genoa, Genoa, Italy.
| | - Monica Frega
- Department of Clinical Neurophysiology, University of Twente, Enschede, the Netherlands.
| | - Anna Fassio
- Department of Experimental Medicine, University of Genoa, Genoa, Italy.
| | - Alberto Lagazzo
- Department of Civil, Chemical and Environmental Engineering (DICCA), University of Genoa, Genoa, Italy.
| | - Sergio Martinoia
- Department of Informatics, Bioengineering, Robotics and Systems Engineering (DIBRIS), University of Genoa, Genoa, Italy.
| | - Laura Pastorino
- Department of Informatics, Bioengineering, Robotics and Systems Engineering (DIBRIS), University of Genoa, Genoa, Italy.
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16
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Urbi B, Lee Y, Hughes I, Thorning S, Broadley SA, Sabet A, Heshmat S. Effects of cannabinoids in Parkinson's disease animal models: a systematic review and meta-analysis. BMJ OPEN SCIENCE 2022; 6:e100302. [PMID: 36618606 PMCID: PMC9812814 DOI: 10.1136/bmjos-2022-100302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 12/06/2022] [Indexed: 12/23/2022] Open
Abstract
Objectives Cannabis has been proposed as a potential treatment for Parkinson's disease (PD) due to its neuroprotective benefits. However, there has been no rigorous review of preclinical studies to evaluate any potential treatment effect. This systematic review was undertaken to provide evidence in support or against a treatment effect of cannabinoids in animal models of PD. Methods Databases were searched for any controlled comparative studies that assessed the effects of any cannabinoid, cannabinoid-based treatment or endocannabinoid transport blocker on behavioural symptoms in PD animal models. Results A total of 41 studies were identified to have met the criteria for this review. 14 of these studies were included in meta-analyses of rotarod, pole and open field tests. Meta-analysis of rotarod tests showed a weighted mean difference of 31.63 s for cannabinoid-treated group compared with control. Meta-analysis of pole tests also showed a positive treatment effect, evidenced by a weighted mean difference of -1.51 s for cannabinoid treat group compared with control. However, meta-analysis of open field test demonstrated a standardised mean difference of only 0.36 indicating no benefit. Conclusion This review demonstrates cannabinoid treatment effects in alleviating motor symptoms of PD animal models and supports the conduct of clinical trials of cannabis in PD population. However, there is no guarantee of successful clinical translation of this outcome because of the many variables that might have affected the results, such as the prevalent unclear and high risk of bias, the different study methods, PD animal models and cannabinoids used.
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Affiliation(s)
- Berzenn Urbi
- Office for Research Governance and Development, Gold Coast University Hospital, Southport, Queensland, Australia,Medicine, Griffith University Faculty of Health, Gold Coast, Queensland, Australia
| | - Yunjoo Lee
- Medicine, Griffith University Faculty of Health, Gold Coast, Queensland, Australia
| | - Ian Hughes
- Office for Research Governance and Development, Gold Coast University Hospital, Southport, Queensland, Australia
| | - Sarah Thorning
- Office for Research Governance and Development, Gold Coast University Hospital, Southport, Queensland, Australia
| | - Simon A Broadley
- Medicine, Griffith University Faculty of Health, Gold Coast, Queensland, Australia,Department of Neurology, Gold Coast University Hospital, Southport, Queensland, Australia
| | - Arman Sabet
- Medicine, Griffith University Faculty of Health, Gold Coast, Queensland, Australia,Department of Neurology, Gold Coast University Hospital, Southport, Queensland, Australia
| | - Saman Heshmat
- Department of Neurology, Gold Coast University Hospital, Southport, Queensland, Australia
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Lee HJ, Choe K, Park JS, Khan A, Kim MW, Park TJ, Kim MO. O-Cyclic Phytosphingosine-1-Phosphate Protects against Motor Dysfunctions and Glial Cell Mediated Neuroinflammation in the Parkinson's Disease Mouse Models. Antioxidants (Basel) 2022; 11:2107. [PMID: 36358479 PMCID: PMC9686509 DOI: 10.3390/antiox11112107] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 10/14/2022] [Accepted: 10/22/2022] [Indexed: 10/29/2023] Open
Abstract
O-cyclic phytosphingosine-1-phosphate (cPS1P) is a novel and chemically synthesized sphingosine metabolite derived from phytosphingosine-1-phosphate (S1P). This study was undertaken to unveil the potential neuroprotective effects of cPS1P on two different mouse models of Parkinson's disease (PD). The study used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and neuron specific enolase promoter human alpha-synuclein (NSE-hαSyn) Korl transgenic mice. MPTP was injected for five consecutive days and cPS1P was injected for alternate days for six weeks intraperitoneally. We performed behavioral tests and analyzed the immunohistochemistry and immunofluorescence staining in the substantia nigra pars compacta (SNpc) and the striatum. The behavior tests showed a significant reduction in the motor functions in the PD models, which was reversed with the administration of cPS1P. In addition, both PD-models showed reduced expression of the sphingosine-1-phosphate receptor 1 (S1PR1), and α-Syn which was restored with cPS1P treatment. In addition, administration of cPS1P restored dopamine-related proteins such as tyrosine hydroxylase (TH), vesicular monoamine transporter 2 (VMAT2), and dopamine transporter (DAT). Lastly, neuroinflammatory related markers such as glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter protein-1 (Iba-1), c-Jun N-terminal kinases (JNK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), tumor necrosis factor-alpha (TNF-α), and interleukin 1 beta (IL-1β) were all reduced after cPS1P administration. The overall findings supported the notion that cPS1P protects against dopamine depletion, neuroinflammation, and PD-associated symptoms.
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Affiliation(s)
- Hyeon Jin Lee
- Division of Life Science and Applied Life Science (BK21 FOUR), College of Natural Sciences, Gyeongsang National University, Jinju 52828, Korea
| | - Kyonghwan Choe
- Division of Life Science and Applied Life Science (BK21 FOUR), College of Natural Sciences, Gyeongsang National University, Jinju 52828, Korea
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, 6229ER Maastricht, The Netherlands
| | - Jun Sung Park
- Division of Life Science and Applied Life Science (BK21 FOUR), College of Natural Sciences, Gyeongsang National University, Jinju 52828, Korea
| | - Amjad Khan
- Division of Life Science and Applied Life Science (BK21 FOUR), College of Natural Sciences, Gyeongsang National University, Jinju 52828, Korea
| | - Min Woo Kim
- Division of Life Science and Applied Life Science (BK21 FOUR), College of Natural Sciences, Gyeongsang National University, Jinju 52828, Korea
| | - Tae Ju Park
- Haemato-oncology/Systems Medicine Group, Paul O’Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary & Life Sciences (MVLS), University of Glasgow, Glasgow G12 0ZD, UK
| | - Myeong Ok Kim
- Division of Life Science and Applied Life Science (BK21 FOUR), College of Natural Sciences, Gyeongsang National University, Jinju 52828, Korea
- Alz-Dementia Korea Co., Jinju 52828, Korea
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18
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Bagnoli S, Fronte B, Bibbiani C, Terzibasi Tozzini E, Cellerino A. Quantification of noradrenergic-, dopaminergic-, and tectal-neurons during aging in the short-lived killifish Nothobranchius furzeri. Aging Cell 2022; 21:e13689. [PMID: 35986561 PMCID: PMC9470901 DOI: 10.1111/acel.13689] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 06/23/2022] [Accepted: 07/27/2022] [Indexed: 01/25/2023] Open
Abstract
Parkinson's disease (PD) is characterized by phosphorylation and aggregation of the protein α-Synuclein and ensuing neuronal death progressing from the noradrenergic locus coeruleus to midbrain dopaminergic neurons. In 2019, Matsui and colleagues reported a spontaneous age-dependent degeneration of dopaminergic neurons and an even greater neurodegeneration of the noradrenergic neurons in the short-lived killifish Nothobranchius furzeri. Given the great possible relevance of a spontaneous model for PD, we assessed neurodegeneration of noradrenergic and dopaminergic neurons in two further laboratory strains of N. furzeri. We implemented, for the first time in N. furzeri, a whole-brain clarification technique and proceeded to entire 3D nuclei reconstruction to quantify total cell numbers in two different stains of N. furzeri. In both strains, we observed that age-dependent neurodegeneration is limited to the locus coeruleus and does not involve the posterior tuberculum. We also applied 3D counting to the optic tectum, an area of active adult neurogenesis, and detected an increase of neurons with age. Our results confirm age-dependent neurodegeneration of noradrenergic neurons, a condition reminiscent of the presymptomatic stage of PD indicating that N. furzeri could be used in the future to identify modifying factors for age-dependent neurodegeneration and open the intriguing possibility that natural genetic variation may influence the susceptibility of dopaminergic neurons.
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Affiliation(s)
- Sara Bagnoli
- Laboratory of Biology (BIO@SNS)Scuola Normale SuperiorePisaItaly
| | | | - Carlo Bibbiani
- Department of Veterinary SciencesUniversity of PisaPisaItaly
| | - Eva Terzibasi Tozzini
- Biology and Evolution of Marine Organisms Dep. (BEOM)Stazione Zoologica Anton DohrnNaplesItaly
| | - Alessandro Cellerino
- Laboratory of Biology (BIO@SNS)Scuola Normale SuperiorePisaItaly,Leibniz Institute on AgingFritz Lipmann InstituteJenaGermany
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19
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Lee Y, Kang JS, Ham OJ, Son MY, Lee MO. Gut metabolite trimethylamine N-oxide induces aging-associated phenotype of midbrain organoids for the induced pluripotent stem cell-based modeling of late-onset disease. Front Aging Neurosci 2022; 14:925227. [PMID: 36051303 PMCID: PMC9426463 DOI: 10.3389/fnagi.2022.925227] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 07/18/2022] [Indexed: 12/01/2022] Open
Abstract
Brain organoids are valuable research models for human development and disease since they mimic the various cell compositions and structures of the human brain; however, they have challenges in presenting aging phenotypes for degenerative diseases. This study analyzed the association between aging and the gut metabolite trimethylamine N-oxide (TMAO), which is highly found in the midbrain of elderly and Parkinson’s disease (PD) patients. TMAO treatment in midbrain organoid induced aging-associated molecular changes, including increased senescence marker expression (P21, P16), p53 accumulation, and epigenetic alterations. In addition, TMAO-treated midbrain organoids have shown parts of neurodegeneration phenotypes, including impaired brain-derived neurotrophic factor (BDNF) signaling, loss of dopaminergic neurons, astrocyte activation, and neuromelanin accumulation. Moreover, we found TMAO treatment-induced pathophysiological phosphorylation of α-synuclein protein at Ser-129 residues and Tau protein at Ser202/Thr205. These results suggest a role of TMAO in the aging and pathogenesis of the midbrain and provide insight into how intestinal dysfunction increases the risk of PD. Furthermore, this system can be utilized as a novel aging model for induced pluripotent stem cell (iPSC)-based modeling of late-onset diseases.
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Affiliation(s)
- Youngsun Lee
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea
- Department of Bioscience, Korea University of Science and Technology (UST), Daejeon, South Korea
| | - Ji Su Kang
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea
- Department of Bioscience, Korea University of Science and Technology (UST), Daejeon, South Korea
| | - On-Ju Ham
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea
| | - Mi-Young Son
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea
- Department of Bioscience, Korea University of Science and Technology (UST), Daejeon, South Korea
- Mi-Young Son,
| | - Mi-Ok Lee
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea
- Department of Bioscience, Korea University of Science and Technology (UST), Daejeon, South Korea
- *Correspondence: Mi-Ok Lee,
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20
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Systemic inflammation biomarkers in 6-OHDA- and LPS-induced Parkinson’s disease in rats. UKRAINIAN BIOCHEMICAL JOURNAL 2022. [DOI: 10.15407/ubj94.01.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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21
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Leukotriene Signaling as a Target in α-Synucleinopathies. Biomolecules 2022; 12:biom12030346. [PMID: 35327537 PMCID: PMC8944962 DOI: 10.3390/biom12030346] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 01/12/2022] [Accepted: 02/12/2022] [Indexed: 01/04/2023] Open
Abstract
Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are two common types of α-synucleinopathies and represent a high unmet medical need. Despite diverging clinical manifestations, both neurodegenerative diseases share several facets of their complex pathophysiology. Apart from α-synuclein aggregation, an impairment of mitochondrial functions, defective protein clearance systems and excessive inflammatory responses are consistently observed in the brains of PD as well as DLB patients. Leukotrienes are lipid mediators of inflammatory signaling traditionally known for their role in asthma. However, recent research advances highlight a possible contribution of leukotrienes, along with their rate-limiting synthesis enzyme 5-lipoxygenase, in the pathogenesis of central nervous system disorders. This review provides an overview of in vitro as well as in vivo studies, in summary suggesting that dysregulated leukotriene signaling is involved in the pathological processes underlying PD and DLB. In addition, we discuss how the leukotriene signaling pathway could serve as a future drug target for the therapy of PD and DLB.
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22
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Sepúlveda D, Cisternas-Olmedo M, Arcos J, Nassif M, Vidal RL. Contribution of Autophagy-Lysosomal Pathway in the Exosomal Secretion of Alpha-Synuclein and Its Impact in the Progression of Parkinson’s Disease. Front Mol Neurosci 2022; 15:805087. [PMID: 35250476 PMCID: PMC8891570 DOI: 10.3389/fnmol.2022.805087] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 01/07/2022] [Indexed: 01/07/2023] Open
Abstract
Parkinson’s disease (PD) is caused by the degeneration of dopaminergic neurons due to an accumulation of intraneuronal abnormal alpha-synuclein (α-syn) protein aggregates. It has been reported that the levels of exosomal α-syn of neuronal origin in plasma correlate significantly with motor dysfunction, highlighting the exosomes containing α-syn as a potential biomarker of PD. In addition, it has been found that the selective autophagy-lysosomal pathway (ALP) contributes to the secretion of misfolded proteins involved in neurodegenerative diseases. In this review, we describe the evidence that supports the relationship between the ALP and α-syn exosomal secretion on the PD progression and its implications in the diagnosis and progression of this pathology.
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Affiliation(s)
- Denisse Sepúlveda
- Center for Integrative Biology, Facultad de Ciencias, Universidad Mayor, Santiago, Chile
- Biomedical Neuroscience Institute, University of Chile, Santiago, Chile
- Geroscience Center for Brain Health and Metabolism, Santiago, Chile
| | - Marisol Cisternas-Olmedo
- Center for Integrative Biology, Facultad de Ciencias, Universidad Mayor, Santiago, Chile
- Biomedical Neuroscience Institute, University of Chile, Santiago, Chile
- Geroscience Center for Brain Health and Metabolism, Santiago, Chile
| | - Javiera Arcos
- Center for Integrative Biology, Facultad de Ciencias, Universidad Mayor, Santiago, Chile
- Biomedical Neuroscience Institute, University of Chile, Santiago, Chile
- Geroscience Center for Brain Health and Metabolism, Santiago, Chile
| | - Melissa Nassif
- Center for Integrative Biology, Facultad de Ciencias, Universidad Mayor, Santiago, Chile
- Escuela de Biotecnología, Facultad de Ciencias, Universidad Mayor, Santiago, Chile
| | - René L. Vidal
- Center for Integrative Biology, Facultad de Ciencias, Universidad Mayor, Santiago, Chile
- Biomedical Neuroscience Institute, University of Chile, Santiago, Chile
- Geroscience Center for Brain Health and Metabolism, Santiago, Chile
- *Correspondence: René L. Vidal,
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23
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Uzair M, Abualait T, Arshad M, Yoo WK, Mir A, Bunyan RF, Bashir S. Transcranial magnetic stimulation in animal models of neurodegeneration. Neural Regen Res 2022; 17:251-265. [PMID: 34269184 PMCID: PMC8464007 DOI: 10.4103/1673-5374.317962] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 12/08/2020] [Accepted: 12/24/2020] [Indexed: 11/13/2022] Open
Abstract
Brain stimulation techniques offer powerful means of modulating the physiology of specific neural structures. In recent years, non-invasive brain stimulation techniques, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation, have emerged as therapeutic tools for neurology and neuroscience. However, the possible repercussions of these techniques remain unclear, and there are few reports on the incisive recovery mechanisms through brain stimulation. Although several studies have recommended the use of non-invasive brain stimulation in clinical neuroscience, with a special emphasis on TMS, the suggested mechanisms of action have not been confirmed directly at the neural level. Insights into the neural mechanisms of non-invasive brain stimulation would unveil the strategies necessary to enhance the safety and efficacy of this progressive approach. Therefore, animal studies investigating the mechanisms of TMS-induced recovery at the neural level are crucial for the elaboration of non-invasive brain stimulation. Translational research done using animal models has several advantages and is able to investigate knowledge gaps by directly targeting neuronal levels. In this review, we have discussed the role of TMS in different animal models, the impact of animal studies on various disease states, and the findings regarding brain function of animal models after TMS in pharmacology research.
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Affiliation(s)
- Mohammad Uzair
- Department of Biological Sciences, Faculty of Basic & Applied Sciences, International Islamic University Islamabad, Pakistan
| | - Turki Abualait
- College of Applied Medical Sciences, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Muhammad Arshad
- Department of Biological Sciences, Faculty of Basic & Applied Sciences, International Islamic University Islamabad, Pakistan
| | - Woo-Kyoung Yoo
- Department of Physical Medicine and Rehabilitation, Hallym University College of Medicine, Anyang, South Korea
- Hallym Institute for Translational Genomics & Bioinformatics, Hallym University College of Medicine, Anyang, South Korea
| | - Ali Mir
- Neuroscience Center, King Fahad Specialist Hospital Dammam, Dammam, Saudi Arabia
| | - Reem Fahd Bunyan
- Neuroscience Center, King Fahad Specialist Hospital Dammam, Dammam, Saudi Arabia
| | - Shahid Bashir
- Neuroscience Center, King Fahad Specialist Hospital Dammam, Dammam, Saudi Arabia
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24
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Anti-Inflammatory Effect of IKK-Activated GSK-3β Inhibitory Peptide Prevented Nigrostriatal Neurodegeneration in the Rodent Model of Parkinson's Disease. Int J Mol Sci 2022; 23:ijms23020998. [PMID: 35055183 PMCID: PMC8779943 DOI: 10.3390/ijms23020998] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/12/2022] [Accepted: 01/14/2022] [Indexed: 12/03/2022] Open
Abstract
Parkinson’s disease (PD) is a progressive movement disorder caused by nigrostriatal neurodegeneration. Since chronically activated neuroinflammation accelerates neurodegeneration in PD, we considered that modulating chronic neuroinflammatory response might provide a novel therapeutic approach. Glycogen synthase kinase 3 (GSK-3) is a multifunctional serine/threonine protein kinase with two isoforms, GSK-3α and GSK-3β, and GSK-3β plays crucial roles in inflammatory response, which include microglial migration and peripheral immune cell activation. GSK-3β inhibitory peptide (IAGIP) is specifically activated by activated inhibitory kappa B kinase (IKK), and its therapeutic effects have been demonstrated in a mouse model of colitis. Here, we investigated whether the anti-inflammatory effects of IAGIP prevent neurodegeneration in the rodent model of PD. IAGIP significantly reduced MPP+-induced astrocyte activation and inflammatory response in primary astrocytes without affecting the phosphorylations of ERK or JNK. In addition, IAGIP inhibited LPS-induced cell migration and p65 activation in BV-2 microglial cells. In vivo study using an MPTP-induced mouse model of PD revealed that intravenous IAGIP effectively prevented motor dysfunction and nigrostriatal neurodegeneration. Our findings suggest that IAGIP has a curative potential in PD models and could offer new therapeutic possibilities for targeting PD.
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25
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Ganesan S, Parvathi VD. Deconstructing the molecular genetics behind the PINK1/Parkin axis in Parkinson’s disease using Drosophila melanogaster as a model organism. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2021. [DOI: 10.1186/s43042-021-00208-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Abstract
Background
Parkinson’s disease (PD) is a multifactorial neurodegenerative disorder marked by the death of nigrostriatal dopaminergic neurons in response to the compounding effects of oxidative stress, mitochondrial dysfunction and protein aggregation. Transgenic Drosophila models have been used extensively to decipher the underlying genetic interactions that exacerbate neural health in PD. Autosomal recessive forms of the disease have been linked to mutations in the serine/threonine kinase PINK1(PTEN-Induced Putative Kinase 1) and E3 ligase Parkin, which function in an axis that is conserved in flies. This review aims to probe the current understanding of PD pathogenesis via the PINK1/Parkin axis while underscoring the importance of several molecular and pharmacologic rescues brought to light through studies in Drosophila.
Main body
Mutations in PINK1 and Parkin have been shown to affect the axonal transport of mitochondria within dopaminergic neurons and perturb the balance between mitochondrial fusion/fission resulting in abnormal mitochondrial morphology. As per studies in flies, ectopic expression of Fwd kinase and Atg-1 to promote fission and mitophagy while suppressing fusion via MUL1 E3 ligase may aid to halt mitochondrial aggregation and prolong the survival of dopaminergic neurons. Furthermore, upregulation of Hsp70/Hsp90 chaperone systems (Trap1, CHIP) to target misfolded mitochondrial respiratory complexes may help to preserve their bioenergetic capacity. Accumulation of reactive oxygen species as a consequence of respiratory complex dysfunction or antioxidant enzyme deficiency further escalates neural death by inducing apoptosis, lipid peroxidation and DNA damage. Fly studies have reported the induction of canonical Wnt signalling to enhance the activity of transcriptional co-activators (PGC1α, FOXO) which induce the expression of antioxidant enzymes. Enhancing the clearance of free radicals via uncoupling proteins (UCP4) has also been reported to ameliorate oxidative stress-induced cell death in PINK1/Parkin mutants.
Conclusion
While these novel mechanisms require validation through mammalian studies, they offer several explanations for the factors propagating dopaminergic death as well as promising insights into the therapeutic importance of transgenic fly models in PD.
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26
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Hu D, Liu Z, Qi X. Mitochondrial Quality Control Strategies: Potential Therapeutic Targets for Neurodegenerative Diseases? Front Neurosci 2021; 15:746873. [PMID: 34867159 PMCID: PMC8633545 DOI: 10.3389/fnins.2021.746873] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Accepted: 10/19/2021] [Indexed: 12/30/2022] Open
Abstract
Many lines of evidence have indicated the therapeutic potential of rescuing mitochondrial integrity by targeting specific mitochondrial quality control pathways in neurodegenerative diseases, such as Parkinson's disease, Huntington's disease, and Alzheimer's disease. In addition to ATP synthesis, mitochondria are critical regulators of ROS production, lipid metabolism, calcium buffering, and cell death. The mitochondrial unfolded protein response, mitochondrial dynamics, and mitophagy are the three main quality control mechanisms responsible for maintaining mitochondrial proteostasis and bioenergetics. The proper functioning of these complex processes is necessary to surveil and restore mitochondrial homeostasis and the healthy pool of mitochondria in cells. Mitochondrial dysfunction occurs early and causally in disease pathogenesis. A significant accumulation of mitochondrial damage resulting from compromised quality control pathways leads to the development of neuropathology. Moreover, genetic or pharmaceutical manipulation targeting the mitochondrial quality control mechanisms can sufficiently rescue mitochondrial integrity and ameliorate disease progression. Thus, therapies that can improve mitochondrial quality control have great promise for the treatment of neurodegenerative diseases. In this review, we summarize recent progress in the field that underscores the essential role of impaired mitochondrial quality control pathways in the pathogenesis of neurodegenerative diseases. We also discuss the translational approaches targeting mitochondrial function, with a focus on the restoration of mitochondrial integrity, including mitochondrial dynamics, mitophagy, and mitochondrial proteostasis.
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Affiliation(s)
- Di Hu
- Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, United States
| | - Zunren Liu
- Department of Biology, College of Arts and Sciences, Case Western Reserve University, Cleveland, OH, United States
| | - Xin Qi
- Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, United States
- Center for Mitochondrial Disease, Case Western Reserve University School of Medicine, Cleveland, OH, United States
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27
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Sun Y, Feng L, Liang L, Stacey GN, Wang C, Wang Y, Hu B. Neuronal cell-based medicines from pluripotent stem cells: Development, production, and preclinical assessment. Stem Cells Transl Med 2021; 10 Suppl 2:S31-S40. [PMID: 34724724 PMCID: PMC8560198 DOI: 10.1002/sctm.20-0522] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 04/21/2021] [Accepted: 06/06/2021] [Indexed: 12/14/2022] Open
Abstract
Brain degeneration and damage is difficult to cure due to the limited endogenous repair capability of the central nervous system. Furthermore, drug development for treatment of diseases of the central nervous system remains a major challenge. However, it now appears that using human pluripotent stem cell-derived neural cells to replace degenerating cells provides a promising cell-based medicine for rejuvenation of brain function. Accordingly, a large number of studies have carried out preclinical assessments, which have involved different neural cell types in several neurological diseases. Recent advances in animal models identify the transplantation of neural derivatives from pluripotent stem cells as a promising path toward the clinical application of cell therapies [Stem Cells Transl Med 2019;8:681-693; Drug Discov Today 2019;24:992-999; Nat Med 2019;25:1045-1053]. Some groups are moving toward clinical testing in humans. However, the difficulty in selection of valuable critical quality criteria for cell products and the lack of functional assays that could indicate suitability for clinical effect continue to hinder neural cell-based medicine development [Biologicals 2019;59:68-71]. In this review, we summarize the current status of preclinical studies progress in this area and outline the biological characteristics of neural cells that have been used in new developing clinical studies. We also discuss the requirements for translation of stem cell-derived neural cells in examples of stem cell-based clinical therapy.
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Affiliation(s)
- Yun Sun
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People's Republic of China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, People's Republic of China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, People's Republic of China
| | - Lin Feng
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People's Republic of China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, People's Republic of China
- National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, People's Republic of China
| | - Lingmin Liang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People's Republic of China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, People's Republic of China
- National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, People's Republic of China
| | - Glyn N Stacey
- National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, People's Republic of China
- International Stem Cell Banking Initiative, Barley, Hertfordshire, UK
| | - Chaoqun Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People's Republic of China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, People's Republic of China
| | - Yukai Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People's Republic of China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, People's Republic of China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, People's Republic of China
- National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, People's Republic of China
| | - Baoyang Hu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People's Republic of China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, People's Republic of China
- National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, People's Republic of China
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28
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Bindas AJ, Kulkarni S, Koppes RA, Koppes AN. Parkinson's disease and the gut: Models of an emerging relationship. Acta Biomater 2021; 132:325-344. [PMID: 33857691 DOI: 10.1016/j.actbio.2021.03.071] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 03/25/2021] [Accepted: 03/30/2021] [Indexed: 12/17/2022]
Abstract
Parkinson's disease (PD) is a common neurodegenerative disease characterized by a progressive loss of fine motor function that impacts 1-2 out of 1,000 people. PD occurs predominately late in life and lacks a definitive biomarker for early detection. Recent cross-disciplinary progress has implicated the gut as a potential origin of PD pathogenesis. The gut-origin hypothesis has motivated research on gut PD pathology and transmission to the brain, especially during the prodromal stage (10-20 years before motor symptom onset). Early findings have revealed several possible triggers for Lewy pathology - the pathological hallmark of PD - in the gut, suggesting that microbiome and epithelial interactions may play a greater than appreciated role. But the mechanisms driving Lewy pathology and gut-brain transmission in PD remain unknown. Development of artificial α-Synuclein aggregates (α-Syn preformed fibrils) and animal disease models have recapitulated features of PD progression, enabling for the first time, controlled investigation of the gut-origin hypothesis. However, the role of specific cells in PD transmission, such as neurons, remains limited and requires in vitro models for controlled evaluation and perturbation. Human cell populations, three-dimensional organoids, and microfluidics as discovery platforms inch us closer to improving existing treatment for patients by providing platforms for discovery and screening. This review includes a discussion of PD pathology, conventional treatments, in vivo and in vitro models, and future directions. STATEMENT OF SIGNIFICANCE: Parkinson's Disease remains a common neurodegenerative disease with palliative versus causal treatments. Recently, the gut-origin hypothesis, where Parkinson's disease is thought to originate and spread from the gut to the brain, has gained traction as a field of investigation. However, despite the wealth of studies and innovative approaches to accelerate the field, there remains a need for in vitro tools to enable fundamental biological understanding of disease progression, and compound screening and efficacy. In this review, we present a historical perspective of Parkinson's Disease pathogenesis, detection, and conventional therapy, animal and human models investigating the gut-origin hypothesis, in vitro models to enable controlled discovery, and future outlooks for this blossoming field.
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Affiliation(s)
- Adam J Bindas
- Department of Chemical Engineering, Northeastern University, 360 Huntington Ave., 313 Snell Engineering, Boston, MA 02115, USA.
| | - Subhash Kulkarni
- Division of Gastroenterology and Hepatology, Johns Hopkins University, 720 Rutland Avenue., Baltimore, MD 21205, USA.
| | - Ryan A Koppes
- Department of Chemical Engineering, Northeastern University, 360 Huntington Ave., 313 Snell Engineering, Boston, MA 02115, USA.
| | - Abigail N Koppes
- Department of Chemical Engineering, Northeastern University, 360 Huntington Ave., 313 Snell Engineering, Boston, MA 02115, USA; Department of Biology, Northeastern University, 360 Huntington Ave., 313 Snell Engineering, Boston, MA 02115, USA.
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29
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Curcuma longa extract ameliorates motor and cognitive deficits of 6-hydroxydopamine-infused Parkinson’s disease model rats. ADVANCES IN TRADITIONAL MEDICINE 2021. [DOI: 10.1007/s13596-021-00606-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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30
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Mottaghi S, Kohl S, Biemann D, Liebana S, Montaño Crespo RE, Buchholz O, Wilson M, Klaus C, Uchenik M, Münkel C, Schmidt R, Hofmann UG. Bilateral Intracranial Beta Activity During Forced and Spontaneous Movements in a 6-OHDA Hemi-PD Rat Model. Front Neurosci 2021; 15:700672. [PMID: 34456673 PMCID: PMC8397450 DOI: 10.3389/fnins.2021.700672] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 07/20/2021] [Indexed: 11/26/2022] Open
Abstract
Cortico-basal ganglia beta oscillations (13–30 Hz) are assumed to be involved in motor impairments in Parkinson’s Disease (PD), especially in bradykinesia and rigidity. Various studies have utilized the unilateral 6-hydroxydopamine (6-OHDA) rat PD model to further investigate PD and test novel treatments. However, a detailed behavioral and electrophysiological characterization of the model, including analyses of popular PD treatments such as DBS, has not been documented in the literature. We hence challenged the 6-OHDA rat hemi-PD model with a series of experiments (i.e., cylinder test, open field test, and rotarod test) aimed at assessing the motor impairments, analyzing the effects of Deep Brain Stimulation (DBS), and identifying under which conditions excessive beta oscillations occur. We found that 6-OHDA hemi-PD rats presented an impaired performance in all experiments compared to the sham group, and DBS could improve their overall performance. Across all the experiments and behaviors, the power in the high beta band was observed to be an important biomarker for PD as it showed differences between healthy and lesioned hemispheres and between 6-OHDA-lesioned and sham rats. This all shows that the 6-OHDA hemi-PD model accurately represents many of the motor and electrophysiological symptoms of PD and makes it a useful tool for the pre-clinical testing of new treatments when low β (13–21 Hz) and high β (21–30 Hz) frequency bands are considered separately.
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Affiliation(s)
- Soheil Mottaghi
- Neuroelectronic Systems, Department of Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany.,Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Technical Faculty, University of Freiburg, Freiburg, Germany
| | - Sandra Kohl
- Neuroelectronic Systems, Department of Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany.,Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Dirk Biemann
- Neuroelectronic Systems, Department of Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany.,Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Samuel Liebana
- Department of Engineering, University of Cambridge, Cambridge, United Kingdom.,Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom
| | - Ruth Eneida Montaño Crespo
- Neuroelectronic Systems, Department of Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany.,Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Oliver Buchholz
- Neuroelectronic Systems, Department of Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany.,Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Mareike Wilson
- Neuroelectronic Systems, Department of Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany.,Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Carolin Klaus
- Neuroelectronic Systems, Department of Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany.,Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Michelle Uchenik
- Biomedical Department, Faculty of Engineering, University of Minnesota, Minneapolis, MN, United States
| | - Christian Münkel
- Neuroelectronic Systems, Department of Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany.,Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Robert Schmidt
- Department of Psychology, The University of Sheffield, Sheffield, United Kingdom
| | - Ulrich G Hofmann
- Neuroelectronic Systems, Department of Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany.,Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Technical Faculty, University of Freiburg, Freiburg, Germany
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31
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Yahi N, Di Scala C, Chahinian H, Fantini J. Innovative treatment targeting gangliosides aimed at blocking the formation of neurotoxic α-synuclein oligomers in Parkinson's disease. Glycoconj J 2021; 39:1-11. [PMID: 34328594 DOI: 10.1007/s10719-021-10012-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/12/2021] [Accepted: 07/14/2021] [Indexed: 12/15/2022]
Abstract
Parkinson's disease (PD) is a major neurodegenerative disorder which exhibits many of the characteristics of a pandemic. Current therapeutic strategies are centered on the dopaminergic system, with limited efficacy, so that a treatment that has a direct impact on the underlying disease pathogenesis is urgently needed. Although α-synuclein is a privileged target for such therapies, this protein has been in the past wrongly considered as exclusively intracellular, so that the impact of paracrine neurotoxicity mechanisms in PD have been largely ignored. In this article we review the data showing that lipid rafts act as plasma membrane machineries for the formation of α-synuclein pore-like oligomers which trigger an increase of intracellular Ca2+. This Ca2+ influx is responsible for a self-sustained cascade of neurotoxic events, including mitochondrial oxidative stress, tau phosphorylation, Ca2+ release from the endoplasmic reticulum, Lewy body formation, and extracellular release of α-synuclein in exosomes. The first step of this cascade is the binding of α-synuclein to lipid raft gangliosides, suggesting that PD should be considered as both a proteinopathy and a ganglioside membrane disorder lipidopathy. Accordingly, blocking α-synuclein-ganglioside interactions should annihilate the whole neurotoxic cascade and stop disease progression. A pipeline of anti-oligomer molecules is under development, among which an in-silico designed synthetic peptide AmyP53 which is the first drug targeting gangliosides and thus able to prevent the formation of α-synuclein oligomers and all downstream neurotoxicity. These new therapeutic avenues challenge the current symptomatic approaches by finally targeting the root cause of PD through a long-awaited paradigm shift.
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Affiliation(s)
- Nouara Yahi
- INSERM UMR_S 1072, Aix-Marseille Université, 13015, Marseille, France
| | - Coralie Di Scala
- Neuroscience Center-HiLIFE, University of Helsinki, 00014, Helsinki, Finland
| | - Henri Chahinian
- INSERM UMR_S 1072, Aix-Marseille Université, 13015, Marseille, France
| | - Jacques Fantini
- INSERM UMR_S 1072, Aix-Marseille Université, 13015, Marseille, France.
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32
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Wood AN. New roles for dopamine in motor skill acquisition: lessons from primates, rodents, and songbirds. J Neurophysiol 2021; 125:2361-2374. [PMID: 33978497 DOI: 10.1152/jn.00648.2020] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Motor learning is a core aspect of human life and appears to be ubiquitous throughout the animal kingdom. Dopamine, a neuromodulator with a multifaceted role in synaptic plasticity, may be a key signaling molecule for motor skill learning. Though typically studied in the context of reward-based associative learning, dopamine appears to be necessary for some types of motor learning. Mesencephalic dopamine structures are highly conserved among vertebrates, as are some of their primary targets within the basal ganglia, a subcortical circuit important for motor learning and motor control. With a focus on the benefits of cross-species comparisons, this review examines how "model-free" and "model-based" computational frameworks for understanding dopamine's role in associative learning may be applied to motor learning. The hypotheses that dopamine could drive motor learning either by functioning as a reward prediction error, through passive facilitating of normal basal ganglia activity, or through other mechanisms are examined in light of new studies using humans, rodents, and songbirds. Additionally, new paradigms that could enhance our understanding of dopamine's role in motor learning by bridging the gap between the theoretical literature on motor learning in humans and other species are discussed.
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Affiliation(s)
- A N Wood
- Department of Biology and Graduate Program in Neuroscience, Emory University, Atlanta, Georgia
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33
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Seo S, Choi CH, Yi KS, Kim SU, Lee K, Choi N, Lee HJ, Cha SH, Kim HN. An engineered neurovascular unit for modeling neuroinflammation. Biofabrication 2021; 13. [PMID: 33849004 DOI: 10.1088/1758-5090/abf741] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 04/13/2021] [Indexed: 12/25/2022]
Abstract
The neurovascular unit (NVU) comprises multiple types of brain cells, including brain endothelial cells, astrocytes, pericytes, neurons, microglia, and oligodendrocytes. Each cell type contributes to the maintenance of the molecular transport barrier and brain tissue homeostasis. Several disorders and diseases of the central nervous system, including neuroinflammation, Alzheimer's disease, stroke, and multiple sclerosis, have been associated with dysfunction of the NVU. As a result, there has been increased demand for the development of NVUin vitromodels. Here, we present a three-dimensional (3D) immortalized human cell-based NVU model generated by organizing the brain microvasculature in a collagen matrix embedded with six different types of cells that comprise the NVU. By surrounding a perfusable brain endothelium with six types of NVU-composing cells, we demonstrated a significant impact of the 3D co-culture on the maturation of barrier function, which is supported by cytokines secreted from NVU-composing cells. Furthermore, NVU-composing cells alleviated the inflammatory responses induced by lipopolysaccharides. Our human cell-based NVUin vitromodel could enable elucidation of both physiological and pathological mechanisms in the human brain and evaluation of safety and efficacy in the context of high-content analysis during the process of drug development.
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Affiliation(s)
- Suyeong Seo
- Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.,Program in Nano Science and Technology, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Republic of Korea.,These authors contributed equally to this work
| | - Chi-Hoon Choi
- Department of Radiology, Chung Buk National University Hospital, Cheongju, Chung Buk, Republic of Korea.,College of Medicine, Chung Buk National University, Cheongju, Chung Buk 28644, Republic of Korea.,These authors contributed equally to this work
| | - Kyung Sik Yi
- Department of Radiology, Chung Buk National University Hospital, Cheongju, Chung Buk, Republic of Korea
| | - Seung U Kim
- Division of Neurology, Department of Medicine, UBC Hospital, University of British Columbia, Vancouver, BC, Canada
| | - Kangwon Lee
- Department of Applied Bioengineering, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Republic of Korea
| | - Nakwon Choi
- Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.,Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology (UST), Seoul 02792, Republic of Korea.,KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea
| | - Hong Jun Lee
- College of Medicine, Chung Buk National University, Cheongju, Chung Buk 28644, Republic of Korea.,Research Institute, eBiogen Inc., Seoul, Republic of Korea
| | - Sang-Hoon Cha
- Department of Radiology, Chung Buk National University Hospital, Cheongju, Chung Buk, Republic of Korea.,College of Medicine, Chung Buk National University, Cheongju, Chung Buk 28644, Republic of Korea
| | - Hong Nam Kim
- Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.,Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology (UST), Seoul 02792, Republic of Korea
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Jo S, Kim SO, Park KW, Lee SH, Hwang YS, Chung SJ. The role of APOE in cognitive trajectories and motor decline in Parkinson's disease. Sci Rep 2021; 11:7819. [PMID: 33837234 PMCID: PMC8035327 DOI: 10.1038/s41598-021-86483-w] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 03/11/2021] [Indexed: 01/10/2023] Open
Abstract
We aimed to investigate the role of the APOE genotype in cognitive and motor trajectories in Parkinson's disease (PD). Using PD registry data, we retrospectively investigated a total of 253 patients with PD who underwent the Mini-Mental State Exam (MMSE) two or more times at least 5 years apart, were aged over 40 years, and free of dementia at the time of enrollment. We performed group-based trajectory modeling to identify patterns of cognitive change using the MMSE. Kaplan-Meier survival analysis was used to investigate the role of the APOE genotype in cognitive and motor progression. Trajectory analysis divided patients into four groups: early fast decline, fast decline, gradual decline, and stable groups with annual MMSE scores decline of - 2.8, - 1.8, - 0.6, and - 0.1 points per year, respectively. The frequency of APOE ε4 was higher in patients in the early fast decline and fast decline groups (50.0%) than those in the stable group (20.1%) (p = 0.007). APOE ε4, in addition to older age at onset, depressive mood, and higher H&Y stage, was associated with the cognitive decline rate, but no APOE genotype was associated with motor progression. APOE genotype could be used to predict the cognitive trajectory in PD.
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Affiliation(s)
- Sungyang Jo
- Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Seon-Ok Kim
- Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, Korea
| | - Kye Won Park
- Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Seung Hyun Lee
- Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Yun Su Hwang
- Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Sun Ju Chung
- Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea.
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Modelling Parkinson's Disease: iPSCs towards Better Understanding of Human Pathology. Brain Sci 2021; 11:brainsci11030373. [PMID: 33799491 PMCID: PMC8000082 DOI: 10.3390/brainsci11030373] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 03/10/2021] [Accepted: 03/10/2021] [Indexed: 02/07/2023] Open
Abstract
Parkinson’s Disease (PD) is a chronic neurodegenerative disorder characterized by motor and non-motor symptoms, among which are bradykinesia, rigidity, tremor as well as mental symptoms such as dementia. The underlying cause of Parkinson disease is degeneration of dopaminergic neurons. It has been challenging to develop an efficient animal model to accurately represent the complex phenotypes found with PD. However, it has become possible to recapitulate the myriad of phenotypes underlying the PD pathology by using human induced pluripotent stem cell (iPSC) technology. Patient-specific iPSC-derived dopaminergic neurons are available and present an opportunity to study many aspects of the PD phenotypes in a dish. In this review, we report the available data on iPSC-derived neurons derived from PD patients with identified gene mutations. Specifically, we will report on the key phenotypes of the generated iPSC-derived neurons from PD patients with different genetic background. Furthermore, we discuss the relationship these cellular phenotypes have to PD pathology and future challenges and prospects for iPSC modelling and understanding of the pathogenesis of PD.
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Vijayanathan Y, Lim SM, Tan MP, Lim FT, Majeed ABA, Ramasamy K. Adult Endogenous Dopaminergic Neuroregeneration Against Parkinson's Disease: Ideal Animal Models? Neurotox Res 2020; 39:504-532. [PMID: 33141428 DOI: 10.1007/s12640-020-00298-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 10/12/2020] [Accepted: 10/13/2020] [Indexed: 11/24/2022]
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disease. The etiology of PD remains an enigma with no available disease modifying treatment or cure. Pharmacological compensation is the only quality of life improving treatments available. Endogenous dopaminergic neuroregeneration has recently been considered a plausible therapeutic strategy for PD. However, researchers have to first decipher the complexity of adult endogenous neuroregeneration. This raises the need of animal models to understand the underlying molecular basis. Mammalian models with highly conserved genetic homology might aid researchers to identify specific molecular mechanisms. However, the scarcity of adult neuroregeneration potential in mammals obfuscates such investigations. Nowadays, non-mammalian models are gaining popularity due to their explicit ability to neuroregenerate naturally without the need of external enhancements, yet these non-mammals have a much diverse gene homology that critical molecular signals might not be conserved across species. The present review highlights the advantages and disadvantages of both mammalian and non-mammalian animal models that can be essentially used to study the potential of endogenous DpN regeneration against PD.
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Affiliation(s)
- Yuganthini Vijayanathan
- Collaborative Drug Discovery Research (CDDR) Group and Brain Degeneration and Therapeutics Group, Faculty of Pharmacy, Universiti Teknologi MARA (UiTM) Cawangan Selangor, Kampus Puncak Alam, 42300, Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia.,Department of Medicine, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia
| | - Siong Meng Lim
- Collaborative Drug Discovery Research (CDDR) Group and Brain Degeneration and Therapeutics Group, Faculty of Pharmacy, Universiti Teknologi MARA (UiTM) Cawangan Selangor, Kampus Puncak Alam, 42300, Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia
| | - Maw Pin Tan
- Department of Medicine, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia
| | - Fei Ting Lim
- Collaborative Drug Discovery Research (CDDR) Group and Brain Degeneration and Therapeutics Group, Faculty of Pharmacy, Universiti Teknologi MARA (UiTM) Cawangan Selangor, Kampus Puncak Alam, 42300, Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia
| | - Abu Bakar Abdul Majeed
- Collaborative Drug Discovery Research (CDDR) Group and Brain Degeneration and Therapeutics Group, Faculty of Pharmacy, Universiti Teknologi MARA (UiTM) Cawangan Selangor, Kampus Puncak Alam, 42300, Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia
| | - Kalavathy Ramasamy
- Collaborative Drug Discovery Research (CDDR) Group and Brain Degeneration and Therapeutics Group, Faculty of Pharmacy, Universiti Teknologi MARA (UiTM) Cawangan Selangor, Kampus Puncak Alam, 42300, Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia.
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37
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Prasad EM, Hung SY. Behavioral Tests in Neurotoxin-Induced Animal Models of Parkinson's Disease. Antioxidants (Basel) 2020; 9:E1007. [PMID: 33081318 PMCID: PMC7602991 DOI: 10.3390/antiox9101007] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 09/21/2020] [Accepted: 09/22/2020] [Indexed: 02/06/2023] Open
Abstract
Currently, neurodegenerative diseases are a major cause of disability around the world. Parkinson's disease (PD) is the second-leading cause of neurodegenerative disorder after Alzheimer's disease. In PD, continuous loss of dopaminergic neurons in the substantia nigra causes dopamine depletion in the striatum, promotes the primary motor symptoms of resting tremor, bradykinesia, muscle rigidity, and postural instability. The risk factors of PD comprise environmental toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular injury, aging, and hereditary defects. The pathologic features of PD include impaired protein homeostasis, mitochondrial dysfunction, nitric oxide, and neuroinflammation, but the interaction of these factors contributing to PD is not fully understood. In neurotoxin-induced PD models, neurotoxins, for instance, 6-hydroxydopamine (6-OHDA), 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-Methyl-4-phenylpyridinium (MPP+), paraquat, rotenone, and permethrin mainly impair the mitochondrial respiratory chain, activate microglia, and generate reactive oxygen species to induce autooxidation and dopaminergic neuronal apoptosis. Since no current treatment can cure PD, using a suitable PD animal model to evaluate PD motor symptoms' treatment efficacy and identify therapeutic targets and drugs are still needed. Hence, the present review focuses on the latest scientific developments in different neurotoxin-induced PD animal models with their mechanisms of pathogenesis and evaluation methods of PD motor symptoms.
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Affiliation(s)
- E. Maruthi Prasad
- Graduate Institute of Acupuncture Science, College of Chinese Medicine, China Medical University, No.91, Hsueh-Shih Road, Taichung 40402, Taiwan;
| | - Shih-Ya Hung
- Graduate Institute of Acupuncture Science, College of Chinese Medicine, China Medical University, No.91, Hsueh-Shih Road, Taichung 40402, Taiwan;
- Department of Medical Research, China Medical University Hospital, No. 2, Yude Road, Taichung 40447, Taiwan
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38
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Park HS, Song YS, Moon BS, Yoo SE, Lee JM, Chung YT, Kim E, Lee BC, Kim SE. Neurorestorative Effects of a Novel Fas-Associated Factor 1 Inhibitor in the MPTP Model: An [ 18F]FE-PE2I Positron Emission Tomography Analysis Study. Front Pharmacol 2020; 11:953. [PMID: 32676027 PMCID: PMC7333457 DOI: 10.3389/fphar.2020.00953] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Accepted: 06/11/2020] [Indexed: 11/13/2022] Open
Abstract
Fas-associated factor 1 (FAF1), a Fas-binding protein, is implicated in neuronal cell death in Parkinson’s disease (PD). We examined the effects of a novel FAF1 inhibitor, KM-819, in dopaminergic neurons in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model using [18F]FE-PE2I positron emission tomography (PET). The MPTP model was generated with subacute MPTP treatment (20 mg/kg/day, i.p.) for 5 consecutive days in C57bl/6J mice. This study included three groups: the control group (treatment with saline only), the MPTP model group with KM-819 treatment (20 mg/kg/day p.o.) for 6 days, and the MPTP model group without KM-819 treatment. [18F]FE-PE2I PET studies were conducted in the same animals before and after MPTP with or without KM-819 treatment to monitor changes in striatal dopamine transporter activity indicated by non-displaceable binding potential (BPND) of [18F]FE-PE2I, and the expression levels of tyrosine hydroxylase were assessed using immunohistochemistry before and after KM-819 treatment. After MPTP injection, decreased striatal BPND was observed in the MPTP model group compared with the control group. Striatal BPND increased in the MPTP model group with KM-819 treatment, but not in the MPTP model group without KM-819 treatment. The tyrosine hydroxylase expression levels also significantly increased in the MPTP model group with KM-819 treatment compared with the control group. This study indicates that inhibition of the Fas-mediated cell death pathway by KM-819 has neurorestorative effects in striatal dopamine neurons in the MPTP model. Further studies would be needed to investigate the potential of KM-819 as a therapeutic drug for PD treatment.
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Affiliation(s)
- Hyun Soo Park
- Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea.,Department of Transdisciplinary Studies Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea
| | - Yoo Sung Song
- Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea
| | - Byung Seok Moon
- Department of Nuclear Medicine, Ewha Womans University Seoul Hospital, Ewha Womans University College of Medicine, Seoul, South Korea
| | | | | | | | - Eunhee Kim
- Department of Bioscience and Biotechnology, Chungnam National University, Daejeon, South Korea
| | - Byung Chul Lee
- Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea.,Department of Transdisciplinary Studies Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea.,Advanced Institutes of Convergence Technology, Suwon, South Korea
| | - Sang Eun Kim
- Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea.,Department of Transdisciplinary Studies Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea.,Advanced Institutes of Convergence Technology, Suwon, South Korea
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39
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Váradi C. Clinical Features of Parkinson's Disease: The Evolution of Critical Symptoms. BIOLOGY 2020; 9:biology9050103. [PMID: 32438686 PMCID: PMC7285080 DOI: 10.3390/biology9050103] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 05/16/2020] [Indexed: 01/19/2023]
Abstract
Parkinson’s disease (PD) is a multi-attribute neurodegenerative disorder combining motor and nonmotor symptoms without well-defined diagnostic clinical markers. The presence of primary motor features (bradykinesia, rest tremor, rigidity and loss of postural reflexes) are the most characteristic signs of PD that are also utilized to identify patients in current clinical practice. The successful implementation of levodopa treatment revealed that nonmotor features are the main contributors of patient disability in PD, and their occurrence might be earlier than motor symptoms during disease progression. Targeted detection of prodromal PD symptoms can open up new possibilities in the identification of PD patients and provide potential patient populations for developing novel neuroprotective therapies. In this review, the evolution of critical features in PD diagnosis is described with special attention to nonmotor symptoms and their possible detection.
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Affiliation(s)
- Csaba Váradi
- Institute of Chemistry, Faculty of Materials Science and Engineering, University of Miskolc, 3515 Miskolc, Hungary
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40
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Sim H, Lee JE, Yoo HM, Cho S, Lee H, Baek A, Kim J, Seo H, Kweon MN, Kim HG, Jeon YJ, Son MY, Kim J. Iroquois Homeobox Protein 2 Identified as a Potential Biomarker for Parkinson's Disease. Int J Mol Sci 2020; 21:E3455. [PMID: 32422864 PMCID: PMC7278941 DOI: 10.3390/ijms21103455] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 05/05/2020] [Accepted: 05/12/2020] [Indexed: 12/12/2022] Open
Abstract
The diagnosis of Parkinson's disease (PD) is initiated after the occurrence of motor symptoms, such as resting tremors, rigidity, and bradykinesia. According to previous reports, non-motor symptoms, notably gastrointestinal dysfunction, could potentially be early biomarkers in PD patients as such symptoms occur earlier than motor symptoms. However, connecting PD to the intestine is methodologically challenging. Thus, we generated in vitro human intestinal organoids from PD patients and ex vivo mouse small intestinal organoids from aged transgenic mice. Both intestinal organoids (IOs) contained the human LRRK2 G2019S mutation, which is the most frequent genetic cause of familial and sporadic PD. By conducting comprehensive genomic comparisons with these two types of IOs, we determined that a particular gene, namely, Iroquois homeobox protein 2 (IRX2), showed PD-related expression patterns not only in human pluripotent stem cell (PSC)-derived neuroectodermal spheres but also in human PSC-derived neuronal cells containing dopaminergic neurons. We expected that our approach of using various cell types presented a novel technical method for studying the effects of multi-organs in PD pathophysiology as well as for the development of diagnostic markers for PD.
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Affiliation(s)
- Hyuna Sim
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea; (H.S.); (J.-E.L.); (S.C.); (H.L.); (A.B.); (Y.-J.J.)
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology, Daejeon 34113, Korea
| | - Joo-Eun Lee
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea; (H.S.); (J.-E.L.); (S.C.); (H.L.); (A.B.); (Y.-J.J.)
| | - Hee Min Yoo
- Group for Biometrology, Korea Research Institute of Standards and Science (KRISS), Daejeon 34113, Korea;
| | - Sunwha Cho
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea; (H.S.); (J.-E.L.); (S.C.); (H.L.); (A.B.); (Y.-J.J.)
| | - Hana Lee
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea; (H.S.); (J.-E.L.); (S.C.); (H.L.); (A.B.); (Y.-J.J.)
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology, Daejeon 34113, Korea
| | - Aruem Baek
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea; (H.S.); (J.-E.L.); (S.C.); (H.L.); (A.B.); (Y.-J.J.)
| | - Jisun Kim
- Department of Molecular & Life Sciences, College of Science & Technology, Hanyang University, Ansan 15588, Korea; (J.K.); (H.S.)
| | - Hyemyung Seo
- Department of Molecular & Life Sciences, College of Science & Technology, Hanyang University, Ansan 15588, Korea; (J.K.); (H.S.)
| | - Mi-Na Kweon
- Mucosal Immunology Laboratory, Department of Convergence Medicine, University of Ulsan College of Medicine/Asan Medical Center, Seoul 05505, Korea;
| | - Hyung Gun Kim
- Department of Pharmacology, College of Medicine, Dankook University, Cheonan 31116, Korea;
| | - Young-Joo Jeon
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea; (H.S.); (J.-E.L.); (S.C.); (H.L.); (A.B.); (Y.-J.J.)
| | - Mi-Young Son
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea; (H.S.); (J.-E.L.); (S.C.); (H.L.); (A.B.); (Y.-J.J.)
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology, Daejeon 34113, Korea
| | - Janghwan Kim
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea; (H.S.); (J.-E.L.); (S.C.); (H.L.); (A.B.); (Y.-J.J.)
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology, Daejeon 34113, Korea
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Genetic predispositions of Parkinson's disease revealed in patient-derived brain cells. NPJ PARKINSONS DISEASE 2020; 6:8. [PMID: 32352027 PMCID: PMC7181694 DOI: 10.1038/s41531-020-0110-8] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Accepted: 03/20/2020] [Indexed: 12/14/2022]
Abstract
Parkinson's disease (PD) is the second most prevalent neurological disorder and has been the focus of intense investigations to understand its etiology and progression, but it still lacks a cure. Modeling diseases of the central nervous system in vitro with human induced pluripotent stem cells (hiPSC) is still in its infancy but has the potential to expedite the discovery and validation of new treatments. Here, we discuss the interplay between genetic predispositions and midbrain neuronal impairments in people living with PD. We first summarize the prevalence of causal Parkinson's genes and risk factors reported in 74 epidemiological and genomic studies. We then present a meta-analysis of 385 hiPSC-derived neuronal lines from 67 recent independent original research articles, which point towards specific impairments in neurons from Parkinson's patients, within the context of genetic predispositions. Despite the heterogeneous nature of the disease, current iPSC models reveal converging molecular pathways underlying neurodegeneration in a range of familial and sporadic forms of Parkinson's disease. Altogether, consolidating our understanding of robust cellular phenotypes across genetic cohorts of Parkinson's patients may guide future personalized drug screens in preclinical research.
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Chang M, Oh B, Choi J, Sulistio YA, Woo H, Jo A, Kim J, Kim E, Kim SW, Hwang J, Park J, Song J, Kwon O, Henry Kim H, Kim Y, Ko JY, Heo JY, Lee MJ, Lee M, Choi M, Chung SJ, Lee H, Lee S. LIN28A loss of function is associated with Parkinson's disease pathogenesis. EMBO J 2019; 38:e101196. [PMID: 31750563 PMCID: PMC6912061 DOI: 10.15252/embj.2018101196] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Revised: 10/01/2019] [Accepted: 10/15/2019] [Indexed: 12/18/2022] Open
Abstract
Parkinson's disease (PD) is neurodegenerative movement disorder characterized by degeneration of midbrain-type dopamine (mDA) neurons in the substantia nigra (SN). The RNA-binding protein Lin28 plays a role in neuronal stem cell development and neuronal differentiation. In this study, we reveal that Lin28 conditional knockout (cKO) mice show degeneration of mDA neurons in the SN, as well as PD-related behavioral deficits. We identify a loss-of-function variant of LIN28A (R192G substitution) in two early-onset PD patients. Using an isogenic human embryonic stem cell (hESC)/human induced pluripotent stem cell (hiPSC)-based disease model, we find that the Lin28 R192G variant leads to developmental defects and PD-related phenotypes in mDA neuronal cells that can be rescued by expression of wild-type Lin28A. Cell transplantation experiments in PD model rats show that correction of the LIN28A variant in the donor patient (pt)-hiPSCs leads to improved behavioral phenotypes. Our data link LIN28A to PD pathogenesis and suggest future personalized medicine targeting this variant in patients.
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Animal Models for Parkinson's Disease Research: Trends in the 2000s. Int J Mol Sci 2019; 20:ijms20215402. [PMID: 31671557 PMCID: PMC6862023 DOI: 10.3390/ijms20215402] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 10/25/2019] [Accepted: 10/28/2019] [Indexed: 12/21/2022] Open
Abstract
Parkinson’s disease (PD) is a chronic and progressive movement disorder and the second most common neurodegenerative disease. Although many studies have been conducted, there is an unmet clinical need to develop new treatments because, currently, only symptomatic therapies are available. To achieve this goal, clarification of the pathology is required. Attempts have been made to emulate human PD and various animal models have been developed over the decades. Neurotoxin models have been commonly used for PD research. Recently, advances in transgenic technology have enabled the development of genetic models that help to identify new approaches in PD research. However, PD animal model trends have not been investigated. Revealing the trends for PD research will be valuable for increasing our understanding of the positive and negative aspects of each model. In this article, we clarified the trends for animal models that were used to research PD in the 2000s, and we discussed each model based on these trends.
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Ke M, Chong CM, Su H. Using induced pluripotent stem cells for modeling Parkinson’s disease. World J Stem Cells 2019; 11:634-649. [PMID: 31616540 PMCID: PMC6789186 DOI: 10.4252/wjsc.v11.i9.634] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 07/26/2019] [Accepted: 08/21/2019] [Indexed: 02/06/2023] Open
Abstract
Parkinson’s disease (PD) is an age-related neurodegenerative disease caused by the progressive loss of dopaminergic (DA) neurons in the substantia nigra. As DA neurons degenerate, PD patients gradually lose their ability of movement. To date no effective therapies are available for the treatment of PD and its pathogenesis remains unknown. Experimental models that appropriately mimic the development of PD are certainly needed for gaining mechanistic insights into PD pathogenesis and identifying new therapeutic targets. Human induced pluripotent stem cells (iPSCs) could provide a promising model for fundamental research and drug screening. In this review, we summarize various iPSCs-based PD models either derived from PD patients through reprogramming technology or established by gene-editing technology, and the promising application of iPSC-based PD models for mechanistic studies and drug testing.
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Affiliation(s)
- Minjing Ke
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
| | - Cheong-Meng Chong
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
| | - Huanxing Su
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
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45
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Patterson JR, Duffy MF, Kemp CJ, Howe JW, Collier TJ, Stoll AC, Miller KM, Patel P, Levine N, Moore DJ, Luk KC, Fleming SM, Kanaan NM, Paumier KL, El-Agnaf OMA, Sortwell CE. Time course and magnitude of alpha-synuclein inclusion formation and nigrostriatal degeneration in the rat model of synucleinopathy triggered by intrastriatal α-synuclein preformed fibrils. Neurobiol Dis 2019; 130:104525. [PMID: 31276792 DOI: 10.1016/j.nbd.2019.104525] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Revised: 06/21/2019] [Accepted: 07/01/2019] [Indexed: 01/22/2023] Open
Abstract
Animal models that accurately recapitulate the accumulation of alpha-synuclein (α-syn) inclusions, progressive neurodegeneration of the nigrostriatal system and motor deficits can be useful tools for Parkinson's disease (PD) research. The preformed fibril (PFF) synucleinopathy model in rodents generally displays these PD-relevant features, however, the magnitude and predictability of these events is far from established. We therefore sought to optimize the magnitude of α-syn accumulation and nigrostriatal degeneration, and to understand the time course of both. Rats were injected unilaterally with different quantities of α-syn PFFs (8 or 16 μg of total protein) into striatal sites selected to concentrate α-syn inclusion formation in the substantia nigra pars compacta (SNpc). Rats displayed an α-syn PFF quantity-dependent increase in the magnitude of ipsilateral SNpc inclusion formation at 2 months and bilateral loss of nigral dopamine neurons at 6 months. Unilateral 16 μg PFF injection also resulted in modest sensorimotor deficits in forelimb adjusting steps associated with degeneration at 6 months. Bilateral injection of 16 μg α-syn PFFs resulted in symmetric bilateral degeneration equivalent to the ipsilateral nigral degeneration observed following unilateral 16 μg PFF injection (~50% loss). Bilateral PFF injections additionally resulted in alterations in several gait analysis parameters. These α-syn PFF parameters can be applied to generate a reproducible synucleinopathy model in rats with which to study pathogenic mechanisms and vet potential disease-modifying therapies.
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Affiliation(s)
- Joseph R Patterson
- Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA.
| | - Megan F Duffy
- Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA; Neuroscience Program, Michigan State University, East Lansing, MI, USA
| | - Christopher J Kemp
- Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA
| | - Jacob W Howe
- Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA
| | - Timothy J Collier
- Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA; Neuroscience Program, Michigan State University, East Lansing, MI, USA; Mercy Health Hauenstein Neuroscience Medical Center, Grand Rapids, MI, USA
| | - Anna C Stoll
- Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
| | - Kathryn M Miller
- Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA; Neuroscience Program, Michigan State University, East Lansing, MI, USA
| | - Pooja Patel
- Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA
| | - Nathan Levine
- Center of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA
| | - Darren J Moore
- Center of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA
| | - Kelvin C Luk
- Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Sheila M Fleming
- College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH, USA
| | - Nicholas M Kanaan
- Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA; Neuroscience Program, Michigan State University, East Lansing, MI, USA; Mercy Health Hauenstein Neuroscience Medical Center, Grand Rapids, MI, USA
| | - Katrina L Paumier
- Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA
| | - Omar M A El-Agnaf
- Neurological Disorders Researcher Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar
| | - Caryl E Sortwell
- Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA; Neuroscience Program, Michigan State University, East Lansing, MI, USA; Mercy Health Hauenstein Neuroscience Medical Center, Grand Rapids, MI, USA
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46
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FTY720 Improves Behavior, Increases Brain Derived Neurotrophic Factor Levels and Reduces α-Synuclein Pathology in Parkinsonian GM2+/- Mice. Neuroscience 2019; 411:1-10. [PMID: 31129200 DOI: 10.1016/j.neuroscience.2019.05.029] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 04/26/2019] [Accepted: 05/14/2019] [Indexed: 12/14/2022]
Abstract
Parkinson's disease (PD) is a progressive aging disorder that affects millions worldwide, thus, disease-modifying-therapies are urgently needed. PD pathology includes α-synuclein (aSyn) accumulation as synucleinopathy. Loss of GM1 gangliosides occurs in PD brain, which is modeled in GM2 synthase transgenic mice. GM2+/- mice have low, not absent GM1 and develop age-onset motor deficits, making them an excellent PD drug testing model. FTY720 (fingolimod) reduces synucleinopathy in A53T aSyn mice and motor dysfunction in 6-OHDA and rotenone PD models, but no one has tested FTY720 in mice that develop age-onset PD-like motor problems. We confirmed that GM2+/-mice had equivalent rotarod, hindlimb reflexes, and adhesive removal functions at 9 mo. From 11 mo, GM2+/- mice received oral FTY720 or vehicle 3x/week to 16 mo. As bladder problems occur in PD, we also assessed GM2+/- bladder function. This allowed us to demonstrate improved motor and bladder function in GM2+/- mice treated with FTY720. By immunoblot, FTY720 reduced levels of proNGF, a biomarker of bladder dysfunction. In humans with PD, arm swing becomes abnormal, and brachial plexus modulates arm swing. Ultrastructure of brachial plexus in wild type and GM2 transgenic mice confirmed abnormal myelination and axons in GM2 transgenics. FTY720 treated GM2+/- brachial plexus sustained myelin associated protein levels and reduced aggregated aSyn and PSer129 aSyn levels. FTY720 increases brain derived neurotrophic factor (BDNF) and we noted increased BDNF in GM2+/- brachial plexus and cerebellum, which contribute to rotarod performance. These findings provide further support for testing low dose FTY720 in patients with PD.
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47
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Lee J, Song K, Huh E, Oh MS, Kim YS. Neuroprotection against 6-OHDA toxicity in PC12 cells and mice through the Nrf2 pathway by a sesquiterpenoid from Tussilago farfara. Redox Biol 2018; 18:6-15. [PMID: 29890337 PMCID: PMC6041377 DOI: 10.1016/j.redox.2018.05.015] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 05/30/2018] [Accepted: 05/30/2018] [Indexed: 12/14/2022] Open
Abstract
Oxidative stress plays a key role in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Therefore, the nuclear factor-E2-related factor 2 (Nrf2), a key regulator of the antioxidative response, is considered to be important as a therapeutic target for neurodegenerative diseases. We investigated the underlying mechanism of Nrf2-mediated neuroprotective effects against oxidative stress in the PC12 cell line by 7β-(3-ethyl-cis-crotonoyloxy)-1α-(2-methylbutyryloxy)-3,14-dehydro-Z-notonipetranone (ECN), one of the sesquiterpenoids in Farfarae Flos. Pretreatment of PC12 cells with ECN had a protective effect against hydrogen peroxide (H2O2)- or 6-hydroxydopamine (6-OHDA)-induced cytotoxicity. ECN upregulated the ARE-luciferase activity and induced the mRNA expression of Nrf2 and antioxidant enzyme heme oxygenase-1 (HO-1). Knockdown of Nrf2 by small, interfering RNA (siRNA) abrogated the upregulation of HO-1, indicating that ECN had induced HO-1 via the Nrf2 pathway. Pretreatment with the thiol reducing agents, N-acetylcysteine (NAC) or dithiothreitol (DTT), attenuated Nrf2 activation and HO-1 expression. However, the non-thiol reducing antioxidant, Trolox, failed to inhibit HO-1 induction by ECN. These results suggest that ECN may directly interact with Kelch-like ECH-associated protein 1 (Keap1) and modify critical cysteine thiols present in the proteins responsible for Nrf2-mediated upregulation of HO-1. In a 6-OHDA-induced mouse model of PD, administration of ECN ameliorated motor impairments and dopaminergic neuronal damage. Taken together, ECN exerts neuroprotective effects by activating the Nrf2/HO-1 signaling pathway in both PC12 cells and mice. Thus, ECN, as an Nrf2 activator, could be an attractive therapeutic candidate for the neuroprotection or treatment of neurodegenerative diseases.
ECN protects PC12 cells against H2O2- or 6-OHDA-induced cell damage. ECN increases HO-1 expression via the nuclear translocation and ARE binding of Nrf2. Activation of the Nrf2/HO-1 pathway contributes to the protective properties of ECN. ECN ameliorates 6-OHDA-induced motor impairments in mice. ECN prevents 6-OHDA-induced loss of dopaminergic neurons in the mouse brain.
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Affiliation(s)
- Joohee Lee
- Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, South Korea
| | - Kwangho Song
- Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, South Korea
| | - Eugene Huh
- Department of Medical Science of Meridian, Graduate School, Kyung Hee University, Seoul 02447, South Korea; Department of Life and Nanopharmaceutical Sciences, Graduate School and Kyung Hee East-West Pharmaceutical Research Institute, Kyung Hee University, Seoul 02447, South Korea
| | - Myung Sook Oh
- Department of Life and Nanopharmaceutical Sciences, Graduate School and Kyung Hee East-West Pharmaceutical Research Institute, Kyung Hee University, Seoul 02447, South Korea
| | - Yeong Shik Kim
- Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, South Korea.
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48
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Costa G, Pinna A, Porceddu PF, Casu MA, Di Maio A, Napolitano F, Usiello A, Morelli M. Rhes Counteracts Dopamine Neuron Degeneration and Neuroinflammation Depending on Gender and Age. Front Aging Neurosci 2018; 10:163. [PMID: 29904346 PMCID: PMC5990628 DOI: 10.3389/fnagi.2018.00163] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Accepted: 05/15/2018] [Indexed: 01/11/2023] Open
Abstract
We have recently shown that male Rhes knockout (KO) mice develop a mild form of spontaneous Parkinson’s disease (PD)-like phenotype, characterized by motor impairment and a decrease in nigrostriatal dopamine (DA) neurons. Experimental evidence has implicated neuroinflammation in PD progression, and the presence of activated glial cells has been correlated with DA neuron degeneration. Despite this, several factors, such as gender, have been found to affect DAergic neuron degeneration and influence neuroinflammation, explaining the differences between men and women in the etiology of PD. On these basis, we studied age and gender differences in DA neuron degeneration and gliosis in the nigrostriatal system of adult (3-month-old) and middle aged (12-month-old) male and female Rhes wild-type (WT) and KO mice. Through immunohistochemistry, tyrosine hydroxylase (TH), microglial (complement type 3 receptor [CD11b]) and astroglial (glial fibrillary acid protein [GFAP]) increase, were evaluated. Adult male Rhes KO mice showed a decrease in TH and an increase in CD11b, both in the caudate putamen (CPu) and substantia nigra pars compacta (SNc), and an increase in GFAP in the CPu. In contrast, adult female Rhes KO mice showed only a decrease in TH in the SNc, whereas no modifications to the levels of GFAP and CD11b were observed in the CPu or SNc. Middle aged male Rhes KO mice showed a decrease in TH in the CPu and SNc, and an increase in GFAP and CD11b in the SNc. Middle aged female Rhes KO mice showed a decrease in TH in the CPu and SNc and an increase in CD11b only in the CPu, but no modifications to GFAP levels. The more marked DA neuron degeneration and neuroinflammation in male compared with female Rhes KO mice, while confirming the role of Rhes as an important protein for DA neuron survival, gives support to Rhes KO mice as a valuable preclinical model for studying the vulnerability factors of DA neuron degeneration as in PD.
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Affiliation(s)
- Giulia Costa
- Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Cagliari, Italy
| | - Annalisa Pinna
- National Research Council of Italy, Neuroscience Institute, Cagliari, Italy
| | - Pier Francesca Porceddu
- Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Cagliari, Italy
| | - Maria Antonietta Casu
- National Research Council of Italy, Institute of Translational Pharmacology, UOS of Cagliari, Scientific and Technological Park of Sardinia POLARIS, Pula, Italy
| | - Anna Di Maio
- IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Francesco Napolitano
- Laboratory of Behavioral Neuroscience, Ceinge Biotecnologie Avanzate, Naples, Italy.,Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy
| | - Alessandro Usiello
- Laboratory of Behavioral Neuroscience, Ceinge Biotecnologie Avanzate, Naples, Italy.,Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania, Caserta, Italy
| | - Micaela Morelli
- Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Cagliari, Italy.,National Research Council of Italy, Neuroscience Institute, Cagliari, Italy.,National Institute of Neuroscience (INN), University of Cagliari, Cagliari, Italy
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49
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Yartsev MM. The emperor's new wardrobe: Rebalancing diversity of animal models in neuroscience research. Science 2018; 358:466-469. [PMID: 29074765 DOI: 10.1126/science.aan8865] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The neuroscience field is steaming ahead, fueled by a revolution in cutting-edge technologies. Concurrently, another revolution has been underway-the diversity of species utilized for neuroscience research is sharply declining, as the field converges on a few selected model organisms. Here, from the perspective of a young scientist, I naively ask: Is the great diversity of questions in neuroscience best studied in only a handful of animal models? I review some of the limitations the field is facing following this convergence and how these can be rectified by increasing the diversity of appropriate model species. I propose that at this exciting time of revolution in genetics and device technologies, neuroscience might be ready to diversify again, if provided the appropriate support.
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Affiliation(s)
- Michael M Yartsev
- Department of Bioengineering and the Helen Wills Neuroscience Institute, University of California-Berkeley, Berkeley, CA 94708, USA.
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50
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Torres N, Molet J, Moro C, Mitrofanis J, Benabid AL. Neuroprotective Surgical Strategies in Parkinson's Disease: Role of Preclinical Data. Int J Mol Sci 2017; 18:ijms18102190. [PMID: 29053638 PMCID: PMC5666871 DOI: 10.3390/ijms18102190] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Revised: 10/10/2017] [Accepted: 10/13/2017] [Indexed: 12/18/2022] Open
Abstract
Although there have been many pharmacological agents considered to be neuroprotective therapy in Parkinson's disease (PD) patients, neurosurgical approaches aimed to neuroprotect or restore the degenerative nigrostriatal system have rarely been the focus of in depth reviews. Here, we explore the neuroprotective strategies involving invasive surgical approaches (NSI) using neurotoxic models 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA), which have led to clinical trials. We focus on several NSI approaches, namely deep brain stimulation of the subthalamic nucleus, glial neurotrophic derived factor (GDNF) administration and cell grafting methods. Although most of these interventions have produced positive results in preclinical animal models, either from behavioral or histological studies, they have generally failed to pass randomized clinical trials to validate each approach. We argue that NSI are promising approaches for neurorestoration in PD, but preclinical studies should be planned carefully in order not only to detect benefits but also to detect potential adverse effects. Further, clinical trials should be designed to be able to detect and disentangle neuroprotection from symptomatic effects. In summary, our review study evaluates the pertinence of preclinical models to study NSI for PD and how this affects their efficacy when translated into clinical trials.
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Affiliation(s)
- Napoleon Torres
- University Grenoble Alpes, CEA, LETI, CLINATEC, MINATEC Campus, 38000 Grenoble, France.
| | - Jenny Molet
- University Grenoble Alpes, CEA, LETI, CLINATEC, MINATEC Campus, 38000 Grenoble, France.
| | - Cecile Moro
- University Grenoble Alpes, CEA, LETI, CLINATEC, MINATEC Campus, 38000 Grenoble, France.
| | - John Mitrofanis
- Department of Anatomy, University of Sydney; Sydney Medical School, Sydney NSW 2006, Australia.
| | - Alim Louis Benabid
- University Grenoble Alpes, CEA, LETI, CLINATEC, MINATEC Campus, 38000 Grenoble, France.
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