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Praveen A, Dougnon G, Matsui H. Exploring α-Syn's Functions Through Ablation Models: Physiological and Pathological Implications. Cell Mol Neurobiol 2025; 45:44. [PMID: 40389720 PMCID: PMC12089638 DOI: 10.1007/s10571-025-01560-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Accepted: 05/07/2025] [Indexed: 05/21/2025]
Abstract
A significant advancement in neurodegenerative research was the discovery that α-synuclein (α-Syn/SNCA) plays a part in the pathophysiology of Parkinson's disease (PD). Decades later, the protein's significant impacts on various brain disorders are still being extensively explored. In disease conditions, α-Syn misfolds and forms abnormal aggregates that accumulate in neurons, thus triggering various organellar dysfunctions and ultimately neurodegeneration. These misfolded forms are highly heterogeneous and vary significantly among different synucleinopathies, such as PD, Multiple System Atrophy, or Dementia with Lewy bodies. Though initially believed to be exclusively localized in the brain, numerous pieces of evidence suggest that α-Syn functions transcend the central nervous system, with roles in peripheral functions, such as modulation of immune responses, hematopoiesis, and gastrointestinal regulation. Here, we aim to provide a detailed compilation of cellular functions and pathological phenotypes that are altered upon attenuation of α-Syn function in vitro and in vivo and explore the effects of SNCA gene silencing in healthy and disease states using cellular and animal models.
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Affiliation(s)
- Anjali Praveen
- Department of Neuroscience of Disease, Brain Research Institute, Niigata University, Niigata, 951-8585, Japan
| | - Godfried Dougnon
- Department of Neuroscience of Disease, Brain Research Institute, Niigata University, Niigata, 951-8585, Japan
| | - Hideaki Matsui
- Department of Neuroscience of Disease, Brain Research Institute, Niigata University, Niigata, 951-8585, Japan.
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Al-Lahham R, Corkins ME, Ishtikhar M, Rabadia P, Ramirez S, Banerjee V, Shahnawaz M. Intracellular Inclusions Induced by Patient-Derived and Amplified α-Synuclein Aggregates Are Morphologically Indistinguishable. Cells 2025; 14:684. [PMID: 40422187 PMCID: PMC12110328 DOI: 10.3390/cells14100684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2025] [Revised: 04/28/2025] [Accepted: 05/06/2025] [Indexed: 05/28/2025] Open
Abstract
Lewy Body Disease (LBD) and Multiple System Atrophy (MSA) are synucleinopathies with distinct prognoses and neuropathologies, however, with overlapping clinical symptoms. Different disease characteristics are proposed to be determined by distinct conformations of alpha-synuclein (α-Syn) aggregates, which can self-propagate and spread between cells via a prion-like mechanism. The goal of this study is to investigate whether α-syn aggregates amplified from brain and CSF samples of LBD and MSA patients using the Seed Amplification Assay (SAA) maintain α-Syn seeding properties similar to those of α-syn aggregates derived from patients' brains. To address this, SAA-amplified and un-amplified α-Syn aggregates from LBD and MSA patients' brains, as well as SAA-amplified α-Syn aggregates from LBD and MSA patients' CSF samples, were used to treat synuclein biosensor cells, and induced intracellular α-Syn inclusions were analyzed by confocal microscopy. Our data indicate that induced α-Syn aggregates from LBD and MSA patients' brains have similar seeding properties and morphological characteristics in the α-Syn biosensor cells as those amplified from LBD and MSA patients' brains, as well as those amplified from LBD and MSA patients' CSF samples. In this study, we demonstrated that, regardless of the source of aggregates, the seeds from LBD and MSA produce cellular accumulation of α-Syn with distinct morphologies, confirming the presence of different conformational strains of α-Syn in LBD and MSA and allowing us to differentiate synucleinopathies based on the morphology of aggregates and seeding properties.
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Affiliation(s)
- Rabab Al-Lahham
- Mitchell Center for Alzheimer’s Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (M.I.); (P.R.); (S.R.)
| | - Mark E. Corkins
- Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA;
| | - Mohd Ishtikhar
- Mitchell Center for Alzheimer’s Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (M.I.); (P.R.); (S.R.)
| | - Prakruti Rabadia
- Mitchell Center for Alzheimer’s Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (M.I.); (P.R.); (S.R.)
| | - Santiago Ramirez
- Mitchell Center for Alzheimer’s Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (M.I.); (P.R.); (S.R.)
| | - Victor Banerjee
- Mitchell Center for Alzheimer’s Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (M.I.); (P.R.); (S.R.)
| | - Mohammad Shahnawaz
- Mitchell Center for Alzheimer’s Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (M.I.); (P.R.); (S.R.)
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Martin LJ, Lee JK, Niedzwiecki MV, Amrein Almira A, Javdan C, Chen MW, Olberding V, Brown SM, Park D, Yohannan S, Putcha H, Zheng B, Garrido A, Benderoth J, Kisner C, Ghaemmaghami J, Northington FJ, Kratimenos P. Hypothermia Shifts Neurodegeneration Phenotype in Neonatal Human Hypoxic-Ischemic Encephalopathy but Not in Related Piglet Models: Possible Relationship to Toxic Conformer and Intrinsically Disordered Prion-like Protein Accumulation. Cells 2025; 14:586. [PMID: 40277911 PMCID: PMC12025496 DOI: 10.3390/cells14080586] [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: 03/14/2025] [Revised: 04/03/2025] [Accepted: 04/10/2025] [Indexed: 04/26/2025] Open
Abstract
Hypothermia (HT) is used clinically for neonatal hypoxic-ischemic encephalopathy (HIE); however, the brain protection is incomplete and selective regional vulnerability and lifelong consequences remain. Refractory damage and impairment with HT cooling/rewarming could result from unchecked or altered persisting cell death and proteinopathy. We tested two hypotheses: (1) HT modifies neurodegeneration type, and (2) intrinsically disordered proteins (IDPs) and encephalopathy cause toxic conformer protein (TCP) proteinopathy neonatally. We studied postmortem human neonatal HIE cases with or without therapeutic HT, neonatal piglets subjected to global hypoxia-ischemia (HI) with and without HT or combinations of HI and quinolinic acid (QA) excitotoxicity surviving for 29-96 h to 14 days, and human oligodendrocytes and neurons exposed to QA for cell models. In human and piglet encephalopathies with normothermia, the neuropathology by hematoxylin and eosin staining was similar; necrotic cell degeneration predominated. With HT, neurodegeneration morphology shifted to apoptosis-necrosis hybrid and apoptotic forms in human HIE, while neurons in HI piglets were unshifting and protected robustly. Oligomers and putative TCPs of α-synuclein (αSyn), nitrated-Syn and aggregated αSyn, misfolded/oxidized superoxide dismutase-1 (SOD1), and prion protein (PrP) were detected with highly specific antibodies by immunohistochemistry, immunofluorescence, and immunoblotting. αSyn and SOD1 TCPs were seen in human HIE brains regardless of HT treatment. αSyn and SOD1 TCPs were detected as early as 29 h after injury in piglets and QA-injured human oligodendrocytes and neurons in culture. Cell immunophenotyping by immunofluorescence showed αSyn detected with antibodies to aggregated/oligomerized protein; nitrated-Syn accumulated in neurons, sometimes appearing as focal dendritic aggregations. Co-localization also showed aberrant αSyn accumulating in presynaptic terminals. Proteinase K-resistant PrP accumulated in ischemic Purkinje cells, and their target regions had PrP-positive neuritic plaque-like pathology. Immunofluorescence revealed misfolded/oxidized SOD1 in neurons, axons, astrocytes, and oligodendrocytes. HT attenuated TCP formation in piglets. We conclude that HT differentially affects brain damage in humans and piglets. HT shifts neuronal cell death to other forms in human while blocking ischemic necrosis in piglet for sustained protection. HI and excitotoxicity also acutely induce formation of TCPs and prion-like proteins from IDPs globally throughout the brain in gray matter and white matter. HT attenuates proteinopathy in piglets but seemingly not in humans. Shifting of cell death type and aberrant toxic protein formation could explain the selective system vulnerability, connectome spreading, and persistent damage seen in neonatal HIE leading to lifelong consequences even after HT treatment.
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Affiliation(s)
- Lee J. Martin
- Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA; (D.P.); (B.Z.)
- Department of Neuroscience, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA
- The Pathobiology Graduate Training Program, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA
| | - Jennifer K. Lee
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA
| | - Mark V. Niedzwiecki
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA
| | - Adriana Amrein Almira
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA
| | - Cameron Javdan
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA
| | - May W. Chen
- Department of Pediatrics, Johns Hopkins University School of Medicine, CMSC, 600 North Wolfe Street, Baltimore, MD 21287-0001, USA
| | - Valerie Olberding
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA
| | - Stephen M. Brown
- The Pathobiology Graduate Training Program, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA
| | - Dongseok Park
- Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA; (D.P.); (B.Z.)
| | - Sophie Yohannan
- Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA; (D.P.); (B.Z.)
| | - Hasitha Putcha
- Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA; (D.P.); (B.Z.)
| | - Becky Zheng
- Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA; (D.P.); (B.Z.)
| | - Annalise Garrido
- Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA; (D.P.); (B.Z.)
| | - Jordan Benderoth
- Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA; (D.P.); (B.Z.)
| | - Chloe Kisner
- Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 20205-2196, USA; (D.P.); (B.Z.)
| | - Javid Ghaemmaghami
- Department of Pediatrics, Children’s National Hospital, George Washington University School of Medicine and Health Sciences, Washington, DC 20010-2916, USA
| | - Frances J. Northington
- Department of Pediatrics, Johns Hopkins University School of Medicine, CMSC, 600 North Wolfe Street, Baltimore, MD 21287-0001, USA
| | - Panagiotis Kratimenos
- Department of Pediatrics, Children’s National Hospital, George Washington University School of Medicine and Health Sciences, Washington, DC 20010-2916, USA
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Liu H, Zhu Q, Wang J, Qin C, Feng R, Wu H, Tang B, Teng J, Ma M, Ding X, Wang X. Assessment of Piezo1 Expression in Urinary Exfoliated Cells as a Diagnostic Indicator for Multiple System Atrophy. Mov Disord 2025; 40:759-764. [PMID: 40008855 DOI: 10.1002/mds.30132] [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: 06/03/2024] [Revised: 01/06/2025] [Accepted: 01/21/2025] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND Multiple system atrophy (MSA) shares clinical features with idiopathic Parkinson' s disease (iPD) and progressive supranuclear palsy (PSP), yet reliable biomarkers for differential diagnosis remain elusive. OBJECTIVES This study aimed to evaluate Piezo1/2 expression in urinary exfoliated cells as a potential biomarker for MSA differentiation. METHODS Piezo1/2 expression levels were quantified in urinary exfoliated cells from 76 MSA patients, 103 iPD patients, 59 PSP patients, and 126 healthy controls (HCs) across three independent cohorts using multiple analytical techniques. RESULTS In the discovery cohort, Piezo1 expression was significantly reduced in MSA patients compared with HCs, iPD, and PSP (area under the curve: 0.9421, 0.8218, and 0.8036, respectively). These findings were validated in two independent cohorts, confirming consistently lower Piezo1 levels in MSA patients and their utility in distinguishing MSA from other groups. CONCLUSION Reduced Piezo1 levels in urinary exfoliated cells show strong potential as a non-invasive biomarker for diagnosing MSA. © 2025 International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Han Liu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Qingyong Zhu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jiuqi Wang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Neurology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, Guangzhou, China
- National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China
| | - Chi Qin
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Renyi Feng
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Neurology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, Guangzhou, China
- National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China
| | - Heng Wu
- Department of Neurology, Multi-Omics Research Center for Brain Disorders, The First Affiliated Hospital, University of South China, Hunan, China
| | - Beisha Tang
- Department of Neurology, Multi-Omics Research Center for Brain Disorders, The First Affiliated Hospital, University of South China, Hunan, China
| | - Junfang Teng
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Mingming Ma
- Department of Neurology, Affiliated People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Henan, China
| | - Xuebing Ding
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Neurology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, Guangzhou, China
- National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China
| | - Xuejing Wang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Neurology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, Guangzhou, China
- National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China
- Department of Neurology, Multi-Omics Research Center for Brain Disorders, The First Affiliated Hospital, University of South China, Hunan, China
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Casini A, Vivacqua G, Ceci L, Leone S, Vaccaro R, Tagliafierro M, Bassi FM, Vitale S, Bocci E, Pannarale L, Carotti S, Franchitto A, Mancini P, Sferra R, Vetuschi A, Latella G, Onori P, Gaudio E, Mancinelli R. TNBS colitis induces architectural changes and alpha-synuclein overexpression in mouse distal colon: A morphological study. Cell Tissue Res 2025; 399:247-265. [PMID: 39656240 PMCID: PMC11787265 DOI: 10.1007/s00441-024-03932-4] [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: 09/24/2024] [Accepted: 11/11/2024] [Indexed: 02/02/2025]
Abstract
Alpha-synuclein (α-syn) is widely expressed in presynaptic neuron terminals, and its structural alterations play an important role in the pathogenesis of Parkinson's disease (PD). Aggregated α-syn has been found in brain, in the peripheral nerves of the enteric nervous system (ENS) and in the intestinal neuroendocrine cells during synucleinopathies and inflammatory bowel disorders. In the present study, we evaluated the histomorphological features of murine colon with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis, a common model of colitis. Thereafter, we investigated the expression of α-syn, Toll-like receptor 4 (TLR4), choline acetyltransferase (ChAT), vasoactive intestinal peptide (VIP), tyrosine hydroxylase (TH), calcitonin gene-related peptide (CGRP), and calcitonin-like receptor (CALCR). Finally, we investigated the presence of phosphorylated α-syn (pS129 α-syn) aggregates and their relationship with inflammatory cells. Colon from TNBS mice showed an increase in inflammatory cells infiltrate and significative changes in the architecture of the intestinal mucosa. α-Syn expression was significantly higher in inflamed colon. VIP was increased in both the mucosa and muscularis externa of TNBS mice, while TH, CGRP, and CALCR were significantly reduced in TNBS mice. Amyloid aggregates of pS129 α-syn were detectable in the ENS, as in the macrophages around the glands of the mucosa correlating with the markers of inflammation. This study describes - for the first time - the altered expression of α-syn and the occurrence of amyloid α-syn aggregates in the inflammatory cells under colitis, supporting the critical role of bowel inflammation in synucleinopathies and the involvement of α-syn in IBD.
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Affiliation(s)
- Arianna Casini
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza University of Rome, Via Alfonso Borelli 50 - 00161, Rome, Italy
| | - Giorgio Vivacqua
- Integrated Research Center (PRAAB), Campus Biomedico University of Rome, Rome, Italy
| | - Ludovica Ceci
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza University of Rome, Via Alfonso Borelli 50 - 00161, Rome, Italy
| | - Stefano Leone
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza University of Rome, Via Alfonso Borelli 50 - 00161, Rome, Italy
| | - Rosa Vaccaro
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza University of Rome, Via Alfonso Borelli 50 - 00161, Rome, Italy
| | - Marco Tagliafierro
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza University of Rome, Via Alfonso Borelli 50 - 00161, Rome, Italy
| | - Filippo Maria Bassi
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza University of Rome, Via Alfonso Borelli 50 - 00161, Rome, Italy
| | - Sara Vitale
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza University of Rome, Via Alfonso Borelli 50 - 00161, Rome, Italy
| | - Emanuele Bocci
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza University of Rome, Via Alfonso Borelli 50 - 00161, Rome, Italy
| | - Luigi Pannarale
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza University of Rome, Via Alfonso Borelli 50 - 00161, Rome, Italy
| | - Simone Carotti
- Integrated Research Center (PRAAB), Campus Biomedico University of Rome, Rome, Italy
| | - Antonio Franchitto
- Division of Health Sciences, Department of Movement, Human and Health Sciences, University of Rome Foro Italico, Rome, Italy
| | - Patrizia Mancini
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Roberta Sferra
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Antonella Vetuschi
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Giovanni Latella
- Division of Gastroenterology, Hepatology and Nutrition, Department of Life, Health & Environmental Sciences, San Salvatore Hospital, University of L'Aquila, L'Aquila, Italy
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza University of Rome, Via Alfonso Borelli 50 - 00161, Rome, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza University of Rome, Via Alfonso Borelli 50 - 00161, Rome, Italy
| | - Romina Mancinelli
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza University of Rome, Via Alfonso Borelli 50 - 00161, Rome, Italy.
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Maristany AJ, Sa BC, Murray C, Subramaniam AB, Oldak SE. Psychiatric Manifestations of Neurological Diseases: A Narrative Review. Cureus 2024; 16:e64152. [PMID: 39119372 PMCID: PMC11308735 DOI: 10.7759/cureus.64152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/09/2024] [Indexed: 08/10/2024] Open
Abstract
Neurological diseases often manifest with psychiatric symptoms, profoundly impacting patients' well-being and treatment outcomes. This comprehensive review examines the psychiatric manifestations associated with Alzheimer's disease, frontotemporal dementia (FTD), Parkinson's disease, multiple sclerosis (MS), stroke, epilepsy, Huntington's disease, amyotrophic lateral sclerosis (ALS), traumatic brain injury (TBI), and multiple system atrophy (MSA). Key psychiatric symptoms include agitation, depression, anxiety, apathy, hallucinations, impulsivity, and aggression across these diseases. In addition, ethical considerations in treating these symptoms are paramount, particularly regarding genetic testing implications, end-of-life discussions, informed consent, and equitable access to innovative treatments. Effective management necessitates interdisciplinary collaboration, personalized interventions, and a focus on patient autonomy. Understanding the psychiatric burden of neurological diseases is crucial for enhancing patients' quality of life. Further research is needed to elucidate underlying mechanisms and develop targeted interventions. This review underscores the importance of comprehensive assessment and ethical treatment practices to address psychiatric manifestations effectively.
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Affiliation(s)
- Anthony J Maristany
- Psychiatry and Behavioral Sciences, University of Miami Leonard M. Miller School of Medicine, Miami, USA
| | - Brianna C Sa
- Psychiatry and Behavioral Sciences, University of Miami Leonard M. Miller School of Medicine, Miami, USA
| | - Cameron Murray
- Psychiatry and Behavioral Sciences, University of Miami Leonard M. Miller School of Medicine, Miami, USA
| | - Ashwin B Subramaniam
- Psychiatry and Behavioral Sciences, University of Miami Leonard M. Miller School of Medicine, Miami, USA
| | - Sean E Oldak
- Psychiatry and Behavioral Sciences, University of Miami Leonard M. Miller School of Medicine/Jackson Memorial Hospital, Miami, USA
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Balusu S, De Strooper B. The necroptosis cell death pathway drives neurodegeneration in Alzheimer's disease. Acta Neuropathol 2024; 147:96. [PMID: 38852117 PMCID: PMC11162975 DOI: 10.1007/s00401-024-02747-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 05/28/2024] [Accepted: 05/28/2024] [Indexed: 06/10/2024]
Abstract
Although apoptosis, pyroptosis, and ferroptosis have been implicated in AD, none fully explains the extensive neuronal loss observed in AD brains. Recent evidence shows that necroptosis is abundant in AD, that necroptosis is closely linked to the appearance of Tau pathology, and that necroptosis markers accumulate in granulovacuolar neurodegeneration vesicles (GVD). We review here the neuron-specific activation of the granulovacuolar mediated neuronal-necroptosis pathway, the potential AD-relevant triggers upstream of this pathway, and the interaction of the necrosome with the endo-lysosomal pathway, possibly providing links to Tau pathology. In addition, we underscore the therapeutic potential of inhibiting necroptosis in neurodegenerative diseases such as AD, as this presents a novel avenue for drug development targeting neuronal loss to preserve cognitive abilities. Such an approach seems particularly relevant when combined with amyloid-lowering drugs.
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Affiliation(s)
- Sriram Balusu
- Laboratory for the Research of Neurodegenerative Diseases, VIB Center for Brain and Disease Research, 3000, Leuven, Belgium.
- Leuven Brain Institute, KU Leuven, 3000, Leuven, Belgium.
| | - Bart De Strooper
- Laboratory for the Research of Neurodegenerative Diseases, VIB Center for Brain and Disease Research, 3000, Leuven, Belgium.
- Leuven Brain Institute, KU Leuven, 3000, Leuven, Belgium.
- UK Dementia Research Institute at UCL, London, WC1E 6BT, UK.
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8
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Sian-Hulsmann J, Riederer P. The 'α-synucleinopathy syndicate': multiple system atrophy and Parkinson's disease. J Neural Transm (Vienna) 2024; 131:585-595. [PMID: 37227594 PMCID: PMC11192696 DOI: 10.1007/s00702-023-02653-2] [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: 03/17/2023] [Accepted: 05/12/2023] [Indexed: 05/26/2023]
Abstract
Multiple System Atrophy (MSA) and Parkinson's diseases (PD) are elite members of the α-synucleinopathy organization. Aberrant accumulations of the protein α-synuclein characterize them. A plethora of evidence indicates the involvement of these rogue inclusions in a cascade of events that disturb cellular homeostasis resulting in neuronal dysfunction. These two neurodegenerative diseases share many features both clinically and pathologically. Cytotoxic processes commonly induced by reactive free radical species have been associated with oxidative stress and neuroinflammation, frequently reported in both diseases. However, it appears they have characteristic and distinct α-synuclein inclusions. It is glial cytoplasmic inclusions in the case of MSA while Lewy bodies manifest in PD. This is probably related to the etiology of the illness. At present, precise mechanism(s) underlying the characteristic configuration of neurodegeneration are unclear. Furthermore, the "prion-like" transmission from cell to cell prompts the suggestion that perhaps these α-synucleinopathies are prion-like diseases. The possibility of some underlying genetic foul play remains controversial. But as major culprits of pathological processes or even single triggers of PD and MSA are the same-like oxidative stress, iron-induced pathology, mitochondriopathy, loss of respiratory activity, loss of proteasomal function, microglial activation, neuroinflammation-it is not farfetched to assume that in sporadic PD and also in MSA a variety of combinations of susceptibility genes contribute to the regional specificity of pathological onset. These players of pathology, as mentioned above, in a synergistic combination, are responsible for driving the progression of PD, MSA and other neurodegenerative disorders. Elucidating the triggers and progression factors is vital for advocating disease modification or halting its progression in both, MSA and PD.
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Affiliation(s)
| | - Peter Riederer
- Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital Würzburg, Würzburg, Germany.
- Department of Psychiatry, University of Southern Denmark Odense, J.B. Winslows Vey 18, 5000, Odense, Denmark.
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Abdul‐Rahman T, Herrera‐Calderón RE, Ahluwalia A, Wireko AA, Ferreira T, Tan JK, Wolfson M, Ghosh S, Horbas V, Garg V, Perveen A, Papadakis M, Ashraf GM, Alexiou A. The potential of phosphorylated α-synuclein as a biomarker for the diagnosis and monitoring of multiple system atrophy. CNS Neurosci Ther 2024; 30:e14678. [PMID: 38572788 PMCID: PMC10993367 DOI: 10.1111/cns.14678] [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: 09/01/2023] [Revised: 02/29/2024] [Accepted: 03/03/2024] [Indexed: 04/05/2024] Open
Abstract
INTRODUCTION Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder characterized by the presence of glial cytoplasmic inclusions (GCIs) containing aggregated α-synuclein (α-Syn). Accurate diagnosis and monitoring of MSA present significant challenges, which can lead to potential misdiagnosis and inappropriate treatment. Biomarkers play a crucial role in improving the accuracy of MSA diagnosis, and phosphorylated α-synuclein (p-syn) has emerged as a promising biomarker for aiding in diagnosis and disease monitoring. METHODS A literature search was conducted on PubMed, Scopus, and Google Scholar using specific keywords and MeSH terms without imposing a time limit. Inclusion criteria comprised various study designs including experimental studies, case-control studies, and cohort studies published only in English, while conference abstracts and unpublished sources were excluded. RESULTS Increased levels of p-syn have been observed in various samples from MSA patients, such as red blood cells, cerebrospinal fluid, oral mucosal cells, skin, and colon biopsies, highlighting their diagnostic potential. The α-Syn RT-QuIC assay has shown sensitivity in diagnosing MSA and tracking its progression. Meta-analyses and multicenter investigations have confirmed the diagnostic value of p-syn in cerebrospinal fluid, demonstrating high specificity and sensitivity in distinguishing MSA from other neurodegenerative diseases. Moreover, combining p-syn with other biomarkers has further improved the diagnostic accuracy of MSA. CONCLUSION The p-syn stands out as a promising biomarker for MSA. It is found in oligodendrocytes and shows a correlation with disease severity and progression. However, further research and validation studies are necessary to establish p-syn as a reliable biomarker for MSA. If proven, p-syn could significantly contribute to early diagnosis, disease monitoring, and assessing treatment response.
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Affiliation(s)
| | | | | | | | - Tomas Ferreira
- Department of Clinical Neurosciences, School of Clinical MedicineUniversity of CambridgeCambridgeUK
| | | | | | - Shankhaneel Ghosh
- Institute of Medical Sciences and SUM Hospital, Siksha 'O' AnusandhanBhubaneswarIndia
| | | | - Vandana Garg
- Department of Pharmaceutical SciencesMaharshi Dayanand UniversityRohtakHaryanaIndia
| | - Asma Perveen
- Glocal School of Life SciencesGlocal UniversitySaharanpurUttar PradeshIndia
- Princess Dr. Najla Bint Saud Al‐Saud Center for Excellence Research in BiotechnologyKing Abdulaziz UniversityJeddahSaudi Arabia
| | - Marios Papadakis
- Department of Surgery II, University Hospital Witten‐HerdeckeUniversity of Witten‐HerdeckeWuppertalGermany
| | - Ghulam Md Ashraf
- Department of Medical Laboratory SciencesUniversity of Sharjah, College of Health Sciences, and Research Institute for Medical and Health SciencesSharjahUAE
| | - Athanasios Alexiou
- University Centre for Research & DevelopmentChandigarh UniversityMohaliPunjabIndia
- Department of Research & DevelopmentAthensGreece
- Department of Research & DevelopmentAFNP MedWienAustria
- Department of Science and EngineeringNovel Global Community Educational FoundationNew South WalesAustralia
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10
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Andersen AM, Kaalund SS, Marner L, Salvesen L, Pakkenberg B, Olesen MV. Quantitative cellular changes in multiple system atrophy brains. Neuropathol Appl Neurobiol 2023; 49:e12941. [PMID: 37812040 DOI: 10.1111/nan.12941] [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: 03/31/2023] [Revised: 09/21/2023] [Accepted: 10/02/2023] [Indexed: 10/10/2023]
Abstract
Multiple system atrophy (MSA) is a neurodegenerative disorder characterised by a combined symptomatology of parkinsonism, cerebellar ataxia, autonomic failure and corticospinal dysfunction. In brains of MSA patients, the hallmark lesion is the aggregation of misfolded alpha-synuclein in oligodendrocytes. Even though the underlying pathological mechanisms remain poorly understood, the evidence suggests that alpha-synuclein aggregation in oligodendrocytes may contribute to the neurodegeneration seen in MSA. The primary aim of this review is to summarise the published stereological data on the total number of neurons and glial cell subtypes (oligodendrocytes, astrocytes and microglia) and volumes in brains from MSA patients. Thus, we include in this review exclusively the reports of unbiased quantitative data from brain regions including the neocortex, nuclei of the cerebrum, the brainstem and the cerebellum. Furthermore, we compare and discuss the stereological results in the context of imaging findings and MSA symptomatology. In general, the stereological results agree with the common neuropathological findings of neurodegeneration and gliosis in brains from MSA patients and support a major loss of nigrostriatal neurons in MSA patients with predominant parkinsonism (MSA-P), as well as olivopontocerebellar atrophy in MSA patients with predominant cerebellar ataxia (MSA-C). Surprisingly, the reports indicate only a minor loss of oligodendrocytes in sub-cortical regions of the cerebrum (glial cells not studied in the cerebellum) and negligible changes in brain volumes. In the past decades, the use of stereological methods has provided a vast amount of accurate information on cell numbers and volumes in the brains of MSA patients. Combining different techniques such as stereology and diagnostic imaging (e.g. MRI, PET and SPECT) with clinical data allows for a more detailed interdisciplinary understanding of the disease and illuminates the relationship between neuropathological changes and MSA symptomatology.
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Affiliation(s)
- Alberte M Andersen
- Centre for Neuroscience and Stereology, Department of Neurology, Bispebjerg-Frederiksberg Hospital, Copenhagen, Denmark
| | - Sanne S Kaalund
- Centre for Neuroscience and Stereology, Department of Neurology, Bispebjerg-Frederiksberg Hospital, Copenhagen, Denmark
| | - Lisbeth Marner
- Department of Clinical Physiology and Nuclear Medicine, Bispebjerg-Frederiksberg Hospital, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Lisette Salvesen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Neurology, Bispebjerg-Frederiksberg Hospital, Copenhagen, Denmark
| | - Bente Pakkenberg
- Centre for Neuroscience and Stereology, Department of Neurology, Bispebjerg-Frederiksberg Hospital, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mikkel V Olesen
- Centre for Neuroscience and Stereology, Department of Neurology, Bispebjerg-Frederiksberg Hospital, Copenhagen, Denmark
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11
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Bai Y, Zhang S, Dong H, Liu Y, Liu C, Zhang X. Advanced Techniques for Detecting Protein Misfolding and Aggregation in Cellular Environments. Chem Rev 2023; 123:12254-12311. [PMID: 37874548 DOI: 10.1021/acs.chemrev.3c00494] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2023]
Abstract
Protein misfolding and aggregation, a key contributor to the progression of numerous neurodegenerative diseases, results in functional deficiencies and the creation of harmful intermediates. Detailed visualization of this misfolding process is of paramount importance for improving our understanding of disease mechanisms and for the development of potential therapeutic strategies. While in vitro studies using purified proteins have been instrumental in delivering significant insights into protein misfolding, the behavior of these proteins in the complex milieu of living cells often diverges significantly from such simplified environments. Biomedical imaging performed in cell provides cellular-level information with high physiological and pathological relevance, often surpassing the depth of information attainable through in vitro methods. This review highlights a variety of methodologies used to scrutinize protein misfolding within biological systems. This includes optical-based methods, strategies leaning on mass spectrometry, in-cell nuclear magnetic resonance, and cryo-electron microscopy. Recent advancements in these techniques have notably deepened our understanding of protein misfolding processes and the features of the resulting misfolded species within living cells. The progression in these fields promises to catalyze further breakthroughs in our comprehension of neurodegenerative disease mechanisms and potential therapeutic interventions.
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Affiliation(s)
- Yulong Bai
- Department of Chemistry, Research Center for Industries of the Future, Westlake University, 600 Dunyu Road, Hangzhou 310030, Zhejiang Province, China
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning 116023, China
| | - Shengnan Zhang
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China
| | - Hui Dong
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China
- University of the Chinese Academy of Sciences, 19 A Yuquan Road, Shijingshan District, Beijing 100049, China
| | - Yu Liu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning 116023, China
| | - Cong Liu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China
- State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Shanghai 200032, China
| | - Xin Zhang
- Department of Chemistry, Research Center for Industries of the Future, Westlake University, 600 Dunyu Road, Hangzhou 310030, Zhejiang Province, China
- Westlake Laboratory of Life Sciences and Biomedicine, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China
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12
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Kim HY, Chia WK, Hsieh CJ, Guarino DS, Graham TJA, Lengyel-Zhand Z, Schneider M, Tomita C, Lougee MG, Kim HJ, Pagar VV, Lee H, Hou C, Garcia BA, Petersson EJ, O’Shea J, Kotzbauer PT, Mathis CA, Lee VMY, Luk KC, Mach RH. A Novel Brain PET Radiotracer for Imaging Alpha Synuclein Fibrils in Multiple System Atrophy. J Med Chem 2023; 66:12185-12202. [PMID: 37651366 PMCID: PMC10617560 DOI: 10.1021/acs.jmedchem.3c00779] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
Abstract
Abnormal α-synuclein (α-syn) aggregation characterizes α-synucleinopathies, including Parkinson's disease (PD) and multiple system atrophy (MSA). However, no suitable positron emission tomography (PET) radiotracer for imaging α-syn in PD and MSA exists currently. Our structure-activity relationship studies identified 4-methoxy-N-(4-(3-(pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)phenyl)benzamide (4i) as a PET radiotracer candidate for imaging α-syn. In vitro assays revealed high binding of 4i to recombinant α-syn fibrils (inhibition constant (Ki) = 6.1 nM) and low affinity for amyloid beta (Aβ) fibrils in Alzheimer's disease (AD) homogenates. However, [3H]4i also exhibited high specific binding to AD, progressive supranuclear palsy, and corticobasal degeneration tissues as well as PD and MSA tissues, suggesting notable affinity to tau. Nevertheless, the specific binding to pathologic α-syn aggregates in MSA post-mortem brain tissues was significantly higher than in PD tissues. This finding demonstrated the potential use of [11C]4i as a PET tracer for imaging α-syn in MSA patients. Nonhuman primate PET studies confirmed good brain uptake and rapid washout for [11C]4i.
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Affiliation(s)
- Ho Young Kim
- Department of Radiology, University of Pennsylvania, Vagelos Laboratories, 1012, 231 S. 34th Street, Philadelphia, PA 19104-6323, USA
| | - Wai Kit Chia
- Department of Radiology, University of Pennsylvania, Vagelos Laboratories, 1012, 231 S. 34th Street, Philadelphia, PA 19104-6323, USA
| | - Chia-Ju Hsieh
- Department of Radiology, University of Pennsylvania, Vagelos Laboratories, 1012, 231 S. 34th Street, Philadelphia, PA 19104-6323, USA
| | - Dinahlee Saturnino Guarino
- Department of Radiology, University of Pennsylvania, Vagelos Laboratories, 1012, 231 S. 34th Street, Philadelphia, PA 19104-6323, USA
| | - Thomas J. A. Graham
- Department of Radiology, University of Pennsylvania, Vagelos Laboratories, 1012, 231 S. 34th Street, Philadelphia, PA 19104-6323, USA
| | - Zsofia Lengyel-Zhand
- Department of Radiology, University of Pennsylvania, Vagelos Laboratories, 1012, 231 S. 34th Street, Philadelphia, PA 19104-6323, USA
| | - Mark Schneider
- Department of Radiology, University of Pennsylvania, Vagelos Laboratories, 1012, 231 S. 34th Street, Philadelphia, PA 19104-6323, USA
| | - Cosette Tomita
- Department of Radiology, University of Pennsylvania, Vagelos Laboratories, 1012, 231 S. 34th Street, Philadelphia, PA 19104-6323, USA
| | - Marshall G. Lougee
- Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
| | - Hee Jong Kim
- Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6303, USA
| | - Vinayak V. Pagar
- Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
| | - Hsiaoju Lee
- Department of Radiology, University of Pennsylvania, Vagelos Laboratories, 1012, 231 S. 34th Street, Philadelphia, PA 19104-6323, USA
| | - Catherine Hou
- Department of Radiology, University of Pennsylvania, Vagelos Laboratories, 1012, 231 S. 34th Street, Philadelphia, PA 19104-6323, USA
| | - Benjamin A. Garcia
- Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6303, USA
| | - E. James Petersson
- Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
| | - Jennifer O’Shea
- Department of Neurology, Washington University School of Medicine, Saint Louis, MO 63110-1010, USA
| | - Paul T. Kotzbauer
- Department of Neurology, Washington University School of Medicine, Saint Louis, MO 63110-1010, USA
| | - Chester A. Mathis
- Department of Radiology, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Virginia M.-Y. Lee
- Center for Neurodegenerative Disease Research, Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104-2676, USA
| | - Kelvin C. Luk
- Center for Neurodegenerative Disease Research, Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104-2676, USA
| | - Robert H. Mach
- Department of Radiology, University of Pennsylvania, Vagelos Laboratories, 1012, 231 S. 34th Street, Philadelphia, PA 19104-6323, USA
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13
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Elnageeb ME, Elfaki I, Adam KM, Ahmed EM, Elkhalifa EM, Abuagla HA, Ahmed AAEM, Ali EW, Eltieb EI, Edris AM. In Silico Evaluation of the Potential Association of the Pathogenic Mutations of Alpha Synuclein Protein with Induction of Synucleinopathies. Diseases 2023; 11:115. [PMID: 37754311 PMCID: PMC10529770 DOI: 10.3390/diseases11030115] [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: 07/30/2023] [Revised: 08/30/2023] [Accepted: 08/31/2023] [Indexed: 09/28/2023] Open
Abstract
Alpha synuclein (α-Syn) is a neuronal protein encoded by the SNCA gene and is involved in the development of Parkinson's disease (PD). The objective of this study was to examine in silico the functional implications of non-synonymous single nucleotide polymorphisms (nsSNPs) in the SNCA gene. We used a range of computational algorithms such as sequence conservation, structural analysis, physicochemical properties, and machine learning. The sequence of the SNCA gene was analyzed, resulting in the mapping of 42,272 SNPs that are classified into different functional categories. A total of 177 nsSNPs were identified within the coding region; there were 20 variants that may influence the α-Syn protein structure and function. This identification was made by employing different analytical tools including SIFT, PolyPhen2, Mut-pred, SNAP2, PANTHER, PhD-SNP, SNP&Go, MUpro, Cosurf, I-Mut, and HOPE. Three mutations, V82A, K80E, and E46K, were selected for further examinations due to their spatial positioning within the α-Syn as determined by PyMol. Results indicated that these mutations may affect the stability and function of α-Syn. Then, a molecular dynamics simulation was conducted for the SNCA wildtype and the four mutant variants (p.A18G, p.V82A, p.K80E, and p.E46K). The simulation examined temperature, pressure, density, root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), solvent-accessible surface area (SASA), and radius of gyration (Rg). The data indicate that the mutations p.V82A, p.K80E, and p.E46K reduce the stability and functionality of α-Syn. These findings highlight the importance of understanding the impact of nsSNPs on α-syn structure and function. Our results required verifications in further protein functional and case-control studies. After being verified these findings can be used in genetic testing for the early diagnosis of PD, the evaluation of the risk factors, and therapeutic approaches.
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Affiliation(s)
- Mohamed E. Elnageeb
- Department of Basic Sciences, College of Applied Medical Sciences, University of Bisha, P.O. Box 551, Bisha 61922, Saudi Arabia
| | - Imadeldin Elfaki
- Department of Biochemistry, Faculty of Science, University of Tabuk, P.O. Box 741, Tabuk 71491, Saudi Arabia
| | - Khalid M. Adam
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, P.O. Box 551, Bisha 61922, Saudi Arabia
| | - Elsadig Mohamed Ahmed
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, P.O. Box 551, Bisha 61922, Saudi Arabia
- Department of Clinical Chemistry, Faculty of Medical Laboratory Sciences, University of El Imam El Mahdi, Kosti 27711, Sudan
| | - Elkhalifa M. Elkhalifa
- Department of Anatomy, Faculty of Medicine and Health Sciences, Nile Valley University, Atbara 46611, Sudan
| | - Hytham A. Abuagla
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, P.O. Box 551, Bisha 61922, Saudi Arabia
| | - Abubakr Ali Elamin Mohamed Ahmed
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, P.O. Box 551, Bisha 61922, Saudi Arabia
| | - Elshazali Widaa Ali
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, P.O. Box 551, Bisha 61922, Saudi Arabia
| | - Elmoiz Idris Eltieb
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, P.O. Box 551, Bisha 61922, Saudi Arabia
| | - Ali M. Edris
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, P.O. Box 551, Bisha 61922, Saudi Arabia
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14
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Liu Z, Lemus J, Smirnova IV, Liu W. Rehabilitation for non-motor symptoms for patients with Parkinson's disease from an α-synuclein perspective: a narrative review. EXPLORATION OF NEUROPROTECTIVE THERAPY 2023; 3:235-257. [PMID: 37920444 PMCID: PMC10621781 DOI: 10.37349/ent.2023.00049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 06/22/2023] [Indexed: 11/04/2023]
Abstract
Parkinson's disease (PD) is a common neurodegenerative disorder affecting aged population around the world. PD is characterized by neuronal Lewy bodies present in the substantia nigra of the midbrain and the loss of dopaminergic neurons with various motor and non-motor symptoms associated with the disease. The protein α-synuclein has been extensively studied for its contribution to PD pathology, as α-synuclein aggregates form the major component of Lewy bodies, a hallmark of PD. In this narrative review, the authors first focus on a brief explanation of α-synuclein aggregation and circumstances under which aggregation can occur, then present a hypothesis for PD pathogenesis in the peripheral nervous system (PNS) and how PD can spread to the central nervous system from the PNS via the transport of α-synuclein aggregates. This article presents arguments both for and against this hypothesis. It also presents various non-pharmacological rehabilitation approaches and management techniques for both motor and non-motor symptoms of PD and the related pathology. This review seeks to examine a possible hypothesis of PD pathogenesis and points to a new research direction focus on rehabilitation therapy for patients with PD. As various non-motor symptoms of PD appear to occur earlier than motor symptoms, more focus on the treatment of non-motor symptoms as well as a better understanding of the biochemical mechanisms behind those non-motor symptoms may lead to better long-term outcomes for patients with PD.
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Affiliation(s)
- Zhaoyang Liu
- Department of Physical Therapy, Rehabilitation Science, and Athletic Training, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Department of Orthopedic Surgery and Sports Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Jessica Lemus
- Department of Physical Therapy, Rehabilitation Science, and Athletic Training, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Irina V. Smirnova
- Department of Physical Therapy, Rehabilitation Science, and Athletic Training, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Wen Liu
- Department of Physical Therapy, Rehabilitation Science, and Athletic Training, University of Kansas Medical Center, Kansas City, KS 66160, USA
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Bicknell B, Liebert A, Borody T, Herkes G, McLachlan C, Kiat H. Neurodegenerative and Neurodevelopmental Diseases and the Gut-Brain Axis: The Potential of Therapeutic Targeting of the Microbiome. Int J Mol Sci 2023; 24:9577. [PMID: 37298527 PMCID: PMC10253993 DOI: 10.3390/ijms24119577] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 04/28/2023] [Accepted: 05/23/2023] [Indexed: 06/12/2023] Open
Abstract
The human gut microbiome contains the largest number of bacteria in the body and has the potential to greatly influence metabolism, not only locally but also systemically. There is an established link between a healthy, balanced, and diverse microbiome and overall health. When the gut microbiome becomes unbalanced (dysbiosis) through dietary changes, medication use, lifestyle choices, environmental factors, and ageing, this has a profound effect on our health and is linked to many diseases, including lifestyle diseases, metabolic diseases, inflammatory diseases, and neurological diseases. While this link in humans is largely an association of dysbiosis with disease, in animal models, a causative link can be demonstrated. The link between the gut and the brain is particularly important in maintaining brain health, with a strong association between dysbiosis in the gut and neurodegenerative and neurodevelopmental diseases. This link suggests not only that the gut microbiota composition can be used to make an early diagnosis of neurodegenerative and neurodevelopmental diseases but also that modifying the gut microbiome to influence the microbiome-gut-brain axis might present a therapeutic target for diseases that have proved intractable, with the aim of altering the trajectory of neurodegenerative and neurodevelopmental diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, autism spectrum disorder, and attention-deficit hyperactivity disorder, among others. There is also a microbiome-gut-brain link to other potentially reversible neurological diseases, such as migraine, post-operative cognitive dysfunction, and long COVID, which might be considered models of therapy for neurodegenerative disease. The role of traditional methods in altering the microbiome, as well as newer, more novel treatments such as faecal microbiome transplants and photobiomodulation, are discussed.
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Affiliation(s)
- Brian Bicknell
- NICM Health Research Institute, University of Western Sydney, Westmead, NSW 2145, Australia; (A.L.); (H.K.)
| | - Ann Liebert
- NICM Health Research Institute, University of Western Sydney, Westmead, NSW 2145, Australia; (A.L.); (H.K.)
- Faculty of Medicine and Health, University of Sydney, Camperdown, NSW 2006, Australia
- Department of Governance and Research, Sydney Adventist Hospital, Wahroonga, NSW 2076, Australia;
| | - Thomas Borody
- Centre for Digestive Diseases, Five Dock, NSW 2046, Australia;
| | - Geoffrey Herkes
- Department of Governance and Research, Sydney Adventist Hospital, Wahroonga, NSW 2076, Australia;
| | - Craig McLachlan
- Centre for Healthy Futures, Torrens University Australia, Ultimo, NSW 2007, Australia;
| | - Hosen Kiat
- NICM Health Research Institute, University of Western Sydney, Westmead, NSW 2145, Australia; (A.L.); (H.K.)
- Centre for Healthy Futures, Torrens University Australia, Ultimo, NSW 2007, Australia;
- Macquarie Medical School, Macquarie University, Macquarie Park, NSW 2109, Australia
- ANU College of Health and Medicine, Australian National University, Canberra, ACT 2601, Australia
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16
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Mitsui J, Matsukawa T, Uemura Y, Kawahara T, Chikada A, Porto KJL, Naruse H, Tanaka M, Ishiura H, Toda T, Kuzuyama H, Hirano M, Wada I, Ga T, Moritoyo T, Takahashi Y, Mizusawa H, Ishikawa K, Yokota T, Kuwabara S, Sawamoto N, Takahashi R, Abe K, Ishihara T, Onodera O, Matsuse D, Yamasaki R, Kira JI, Katsuno M, Hanajima R, Ogata K, Takashima H, Matsushima M, Yabe I, Sasaki H, Tsuji S. High-dose ubiquinol supplementation in multiple-system atrophy: a multicentre, randomised, double-blinded, placebo-controlled phase 2 trial. EClinicalMedicine 2023; 59:101920. [PMID: 37256098 PMCID: PMC10225719 DOI: 10.1016/j.eclinm.2023.101920] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/03/2023] [Accepted: 03/07/2023] [Indexed: 06/01/2023] Open
Abstract
Background Functionally impaired variants of COQ2, encoding an enzyme in biosynthesis of coenzyme Q10 (CoQ10), were found in familial multiple system atrophy (MSA) and V393A in COQ2 is associated with sporadic MSA. Furthermore, reduced levels of CoQ10 have been demonstrated in MSA patients. Methods This study was a multicentre, randomised, double-blinded, placebo-controlled phase 2 trial. Patients with MSA were randomly assigned (1:1) to either ubiquinol (1500 mg/day) or placebo. The primary efficacy outcome was the change in the unified multiple system atrophy rating scale (UMSARS) part 2 at 48 weeks. Efficacy was assessed in all patients who completed at least one efficacy assessment (full analysis set). Safety analyses included patients who completed at least one dose of investigational drug. This trial is registered with UMIN-CTR (UMIN000031771), where the drug name of MSA-01 was used to designate ubiquinol. Findings Between June 26, 2018, and May 27, 2019, 139 patients were enrolled and randomly assigned to the ubiquinol group (n = 69) or the placebo group (n = 70). A total of 131 patients were included in the full analysis set (63 in the ubiquinol group; 68 in the placebo group). This study met the primary efficacy outcome (least square mean difference in UMSARS part 2 score (-1.7 [95% CI, -3.2 to -0.2]; P = 0.023)). The ubiquinol group also showed better secondary efficacy outcomes (Barthel index, Scale for the Assessment and Rating of Ataxia, and time required to walk 10 m). Rates of adverse events potentially related to the investigational drug were comparable between ubiquinol (n = 15 [23.8%]) and placebo (n = 21 [30.9%]). Interpretation High-dose ubiquinol was well-tolerated and led to a significantly smaller decline of UMSARS part 2 score compared with placebo. Funding Japan Agency for Medical Research and Development.
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Affiliation(s)
- Jun Mitsui
- Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takashi Matsukawa
- Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yukari Uemura
- Department of Data Sciences, Biostatistics Section, National Center for Global Health and Medicine, Tokyo, Japan
| | - Takuya Kawahara
- Clinical Research Promotion Center, The University of Tokyo Hospital, Tokyo, Japan
| | - Ayaka Chikada
- Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kristine Joyce L. Porto
- Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroya Naruse
- Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masaki Tanaka
- Institute of Medical Genomics, International University of Health and Welfare, Narita, Japan
| | - Hiroyuki Ishiura
- Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tatsushi Toda
- Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Haruko Kuzuyama
- Clinical Research Promotion Center, The University of Tokyo Hospital, Tokyo, Japan
| | - Mari Hirano
- Clinical Research Promotion Center, The University of Tokyo Hospital, Tokyo, Japan
| | - Ikue Wada
- Clinical Research Promotion Center, The University of Tokyo Hospital, Tokyo, Japan
| | - Toshio Ga
- Clinical Research Promotion Center, The University of Tokyo Hospital, Tokyo, Japan
| | - Takashi Moritoyo
- Clinical Research Promotion Center, The University of Tokyo Hospital, Tokyo, Japan
| | - Yuji Takahashi
- Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry (NCNP), Kodaira, Japan
| | - Hidehiro Mizusawa
- Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry (NCNP), Kodaira, Japan
| | - Kinya Ishikawa
- Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences and Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan
| | - Takanori Yokota
- Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences and Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan
| | - Satoshi Kuwabara
- Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Nobukatsu Sawamoto
- Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Ryosuke Takahashi
- Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Koji Abe
- Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Tomohiko Ishihara
- Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
| | - Osamu Onodera
- Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
| | - Dai Matsuse
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Ryo Yamasaki
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Jun-Ichi Kira
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masahisa Katsuno
- Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Ritsuko Hanajima
- Division of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan
| | - Katsuhisa Ogata
- Department of Neurology, National Hospital Organization Higashisaitama National Hospital, Hasuda, Japan
| | - Hiroshi Takashima
- Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Masaaki Matsushima
- Department of Neurology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Ichiro Yabe
- Department of Neurology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Hidenao Sasaki
- Department of Neurology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Shoji Tsuji
- Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Institute of Medical Genomics, International University of Health and Welfare, Narita, Japan
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17
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Anselmi C, Caicci F, Bocci T, Guidetti M, Priori A, Giusti V, Levy T, Raveh T, Voskoboynik A, Weissman IL, Manni L. Multiple Forms of Neural Cell Death in the Cyclical Brain Degeneration of A Colonial Chordate. Cells 2023; 12:1041. [PMID: 37048113 PMCID: PMC10093557 DOI: 10.3390/cells12071041] [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: 02/24/2023] [Revised: 03/20/2023] [Accepted: 03/24/2023] [Indexed: 03/31/2023] Open
Abstract
Human neuronal loss occurs through different cellular mechanisms, mainly studied in vitro. Here, we characterized neuronal death in B. schlosseri, a marine colonial tunicate that shares substantial genomic homology with mammals and has a life history in which controlled neurodegeneration happens simultaneously in the brains of adult zooids during a cyclical phase named takeover. Using an ultrastructural and transcriptomic approach, we described neuronal death forms in adult zooids before and during the takeover phase while comparing adult zooids in takeover with their buds where brains are refining their structure. At takeover, we found in neurons clear morphologic signs of apoptosis (i.e., chromatin condensation, lobed nuclei), necrosis (swollen cytoplasm) and autophagy (autophagosomes, autolysosomes and degradative multilamellar bodies). These results were confirmed by transcriptomic analyses that highlighted the specific genes involved in these cell death pathways. Moreover, the presence of tubulovesicular structures in the brain medulla alongside the over-expression of prion disease genes in late cycle suggested a cell-to-cell, prion-like propagation recalling the conformational disorders typical of some human neurodegenerative diseases. We suggest that improved understanding of how neuronal alterations are regulated in the repeated degeneration-regeneration program of B. schlosseri may yield mechanistic insights relevant to the study of human neurodegenerative diseases.
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Affiliation(s)
- Chiara Anselmi
- Hopkins Marine Station, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Pacific Grove, CA 93950, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
- Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, USA
| | - Federico Caicci
- Dipartimento di Biologia, Università degli Studi di Padova, 35131 Padova, Italy
| | - Tommaso Bocci
- “Aldo Ravelli” Center for Neurotechnology and Experimental Brain Therapeutics, Department of Health Sciences, University of Milan, 20142 Milan, Italy
| | - Matteo Guidetti
- “Aldo Ravelli” Center for Neurotechnology and Experimental Brain Therapeutics, Department of Health Sciences, University of Milan, 20142 Milan, Italy
- Department of Electronics, Information and Bioengineering, Politecnico di Milano, 20133 Milan, Italy
| | - Alberto Priori
- “Aldo Ravelli” Center for Neurotechnology and Experimental Brain Therapeutics, Department of Health Sciences, University of Milan, 20142 Milan, Italy
| | | | - Tom Levy
- Hopkins Marine Station, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Pacific Grove, CA 93950, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Tal Raveh
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Ayelet Voskoboynik
- Hopkins Marine Station, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Pacific Grove, CA 93950, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
- Chan Zuckerberg Biohub, San Francisco, CA 94158, USA
| | - Irving L. Weissman
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Lucia Manni
- Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, USA
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18
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Sun S, Wang C, Zhao P, Kline GM, Grandjean JMD, Jiang X, Labaudiniere R, Wiseman RL, Kelly JW, Balch WE. Capturing the conversion of the pathogenic alpha-1-antitrypsin fold by ATF6 enhanced proteostasis. Cell Chem Biol 2023; 30:22-42.e5. [PMID: 36630963 PMCID: PMC9930901 DOI: 10.1016/j.chembiol.2022.12.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 11/07/2022] [Accepted: 12/19/2022] [Indexed: 01/12/2023]
Abstract
Genetic variation in alpha-1 antitrypsin (AAT) causes AAT deficiency (AATD) through liver aggregation-associated gain-of-toxic pathology and/or insufficient AAT activity in the lung manifesting as chronic obstructive pulmonary disease (COPD). Here, we utilize 71 AATD-associated variants as input through Gaussian process (GP)-based machine learning to study the correction of AAT folding and function at a residue-by-residue level by pharmacological activation of the ATF6 arm of the unfolded protein response (UPR). We show that ATF6 activators increase AAT neutrophil elastase (NE) inhibitory activity, while reducing polymer accumulation for the majority of AATD variants, including the prominent Z variant. GP-based profiling of the residue-by-residue response to ATF6 activators captures an unexpected role of the "gate" area in managing AAT-specific activity. Our work establishes a new spatial covariant (SCV) understanding of the convertible state of the protein fold in response to genetic perturbation and active environmental management by proteostasis enhancement for precision medicine.
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Affiliation(s)
- Shuhong Sun
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
| | - Chao Wang
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
| | - Pei Zhao
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
| | - Gabe M Kline
- Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA
| | | | - Xin Jiang
- Protego Biopharma, 10945 Vista Sorrento Parkway, San Diego, CA, USA
| | | | - R Luke Wiseman
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
| | - Jeffery W Kelly
- Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA
| | - William E Balch
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA.
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19
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Mushroom Natural Products in Neurodegenerative Disease Drug Discovery. Cells 2022; 11:cells11233938. [PMID: 36497196 PMCID: PMC9740391 DOI: 10.3390/cells11233938] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 11/21/2022] [Accepted: 11/23/2022] [Indexed: 12/12/2022] Open
Abstract
The variety of drugs available to treat neurodegenerative diseases is limited. Most of these drug's efficacy is restricted by individual genetics and disease stages and usually do not prevent neurodegeneration acting long after irreversible damage has already occurred. Thus, drugs targeting the molecular mechanisms underlying subsequent neurodegeneration have the potential to negate symptom manifestation and subsequent neurodegeneration. Neuroinflammation is a common feature of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis, and is associated with the activation of the NLRP3 inflammasome, which in turn leads to neurodegeneration. Inflammasome activation and oligomerisation is suggested to be a major driver of disease progression occurring in microglia. With several natural products and natural product derivatives currently in clinical trials, mushrooms have been highlighted as a rich and largely untapped source of biologically active compounds in both in vitro and in vivo neurodegenerative disease models, partially supported by successful clinical trial evaluations. Additionally, novel high-throughput methods for the screening of natural product compound libraries are being developed to help accelerate the neurodegenerative disease drug discovery process, targeting neuroinflammation. However, the breadth of research relating to mushroom natural product high-throughput screening is limited, providing an exciting opportunity for further detailed investigations.
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20
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Kinoshita C, Kubota N, Aoyama K. Glutathione Depletion and MicroRNA Dysregulation in Multiple System Atrophy: A Review. Int J Mol Sci 2022; 23:15076. [PMID: 36499400 PMCID: PMC9740333 DOI: 10.3390/ijms232315076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/25/2022] [Accepted: 11/29/2022] [Indexed: 12/02/2022] Open
Abstract
Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by parkinsonism, cerebellar impairment, and autonomic failure. Although the causes of MSA onset and progression remain uncertain, its pathogenesis may involve oxidative stress via the generation of excess reactive oxygen species and/or destruction of the antioxidant system. One of the most powerful antioxidants is glutathione, which plays essential roles as an antioxidant enzyme cofactor, cysteine-storage molecule, major redox buffer, and neuromodulator, in addition to being a key antioxidant in the central nervous system. Glutathione levels are known to be reduced in neurodegenerative diseases. In addition, genes regulating redox states have been shown to be post-transcriptionally modified by microRNA (miRNA), one of the most important types of non-coding RNA. miRNAs have been reported to be dysregulated in several diseases, including MSA. In this review, we focused on the relation between glutathione deficiency, miRNA dysregulation and oxidative stress and their close relation with MSA pathology.
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Affiliation(s)
- Chisato Kinoshita
- Department of Pharmacology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan
| | - Noriko Kubota
- Department of Pharmacology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan
- Teikyo University Support Center for Women Physicians and Researchers, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan
| | - Koji Aoyama
- Department of Pharmacology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan
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21
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Synucleinopathy in Amyotrophic Lateral Sclerosis: A Potential Avenue for Antisense Therapeutics? Int J Mol Sci 2022; 23:ijms23169364. [PMID: 36012622 PMCID: PMC9409035 DOI: 10.3390/ijms23169364] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/17/2022] [Accepted: 08/18/2022] [Indexed: 01/02/2023] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease classified as both a neurodegenerative and neuromuscular disorder. With a complex aetiology and no current cure for ALS, broadening the understanding of disease pathology and therapeutic avenues is required to progress with patient care. Alpha-synuclein (αSyn) is a hallmark for disease in neurodegenerative disorders, such as Parkinson's disease, Lewy body dementia, and multiple system atrophy. A growing body of evidence now suggests that αSyn may also play a pathological role in ALS, with αSyn-positive Lewy bodies co-aggregating alongside known ALS pathogenic proteins, such as SOD1 and TDP-43. This review endeavours to capture the scope of literature regarding the aetiology and development of ALS and its commonalities with "synucleinopathy disorders". We will discuss the involvement of αSyn in ALS and motor neuron disease pathology, and the current theories and strategies for therapeutics in ALS treatment, as well as those targeting αSyn for synucleinopathies, with a core focus on small molecule RNA technologies.
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22
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Sidoroff V, Bower P, Stefanova N, Fanciulli A, Stankovic I, Poewe W, Seppi K, Wenning GK, Krismer F. Disease-Modifying Therapies for Multiple System Atrophy: Where Are We in 2022? JOURNAL OF PARKINSON'S DISEASE 2022; 12:1369-1387. [PMID: 35491799 PMCID: PMC9398078 DOI: 10.3233/jpd-223183] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Multiple system atrophy is a rapidly progressive and fatal neurodegenerative disorder. While numerous preclinical studies suggested efficacy of potentially disease modifying agents, none of those were proven to be effective in large-scale clinical trials. Three major strategies are currently pursued in preclinical and clinical studies attempting to slow down disease progression. These target α-synuclein, neuroinflammation, and restoration of neurotrophic support. This review provides a comprehensive overview on ongoing preclinical and clinical developments of disease modifying therapies. Furthermore, we will focus on potential shortcomings of previous studies that can be avoided to improve data quality in future studies of this rare disease.
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Affiliation(s)
- Victoria Sidoroff
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Pam Bower
- The Multiple System Atrophy Coalition, Inc., McLean, VA, USA
| | - Nadia Stefanova
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | | | - Iva Stankovic
- Neurology Clinic, University Clinical Center of Serbia, School of Medicine, University of Belgrade, Belgrade, Serbia
| | - Werner Poewe
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Klaus Seppi
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Gregor K Wenning
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Florian Krismer
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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23
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Jellinger KA. Heterogeneity of Multiple System Atrophy: An Update. Biomedicines 2022; 10:599. [PMID: 35327402 PMCID: PMC8945102 DOI: 10.3390/biomedicines10030599] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 02/24/2022] [Accepted: 03/02/2022] [Indexed: 02/04/2023] Open
Abstract
Multiple system atrophy (MSA) is a fatal, rapidly progressing neurodegenerative disease of uncertain etiology, clinically characterized by various combinations of Levodopa unresponsive parkinsonism, cerebellar, autonomic and motor dysfunctions. The morphological hallmark of this α-synucleinopathy is the deposition of aberrant α-synuclein in both glia, mainly oligodendroglia (glial cytoplasmic inclusions /GCIs/) and neurons, associated with glioneuronal degeneration of the striatonigral, olivopontocerebellar and many other neuronal systems. Typical phenotypes are MSA with predominant parkinsonism (MSA-P) and a cerebellar variant (MSA-C) with olivocerebellar atrophy. However, MSA can present with a wider range of clinical and pathological features than previously thought. In addition to rare combined or "mixed" MSA, there is a broad spectrum of atypical MSA variants, such as those with a different age at onset and disease duration, "minimal change" or prodromal forms, MSA variants with Lewy body disease or severe hippocampal pathology, rare forms with an unusual tau pathology or spinal myoclonus, an increasing number of MSA cases with cognitive impairment/dementia, rare familial forms, and questionable conjugal MSA. These variants that do not fit into the current classification of MSA are a major challenge for the diagnosis of this unique proteinopathy. Although the clinical diagnostic accuracy and differential diagnosis of MSA have improved by using combined biomarkers, its distinction from clinically similar extrapyramidal disorders with other pathologies and etiologies may be difficult. These aspects should be taken into consideration when revising the current diagnostic criteria. This appears important given that disease-modifying treatment strategies for this hitherto incurable disorder are under investigation.
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Affiliation(s)
- Kurt A Jellinger
- Institute of Clinical Neurobiology, Alberichgasse 5/13, A-1150 Vienna, Austria
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24
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The Alpha-Synuclein RT-QuIC Products Generated by the Olfactory Mucosa of Patients with Parkinson’s Disease and Multiple System Atrophy Induce Inflammatory Responses in SH-SY5Y Cells. Cells 2021; 11:cells11010087. [PMID: 35011649 PMCID: PMC8750063 DOI: 10.3390/cells11010087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 12/22/2021] [Accepted: 12/24/2021] [Indexed: 11/28/2022] Open
Abstract
Parkinson’s disease (PD) and multiple system atrophy (MSA) are caused by two distinct strains of disease-associated α-synuclein (αSynD). Recently, we have shown that olfactory mucosa (OM) samples of patients with PD and MSA can seed the aggregation of recombinant α-synuclein by means of Real-Time Quaking-Induced Conversion (αSyn_RT-QuIC). Remarkably, the biochemical and morphological properties of the final α-synuclein aggregates significantly differed between PD and MSA seeded samples. Here, these aggregates were given to neuron-like differentiated SH-SY5Y cells and distinct inflammatory responses were observed. To deepen whether the morphological features of α-synuclein aggregates were responsible for this variable SH-SY5Y inflammatory response, we generated three biochemically and morphologically distinct α-synuclein aggregates starting from recombinant α-synuclein that were used to seed αSyn_RT-QuIC reaction; the final reaction products were used to stimulate SH-SY5Y cells. Our study showed that, in contrast to OM samples of PD and MSA patients, the artificial aggregates did not transfer their distinctive features to the αSyn_RT-QuIC products and the latter induced analogous inflammatory responses in cells. Thus, the natural composition of the αSynD strains but also other specific factors in OM tissue can substantially modulate the biochemical, morphological and inflammatory features of the αSyn_RT-QuIC products.
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25
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Barker RA. The Origins of the Protein Spread in Parkinson's Disease. Mov Disord Clin Pract 2021; 8:1194-1197. [PMID: 34765685 DOI: 10.1002/mdc3.13314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 07/05/2021] [Indexed: 11/10/2022] Open
Affiliation(s)
- Roger A Barker
- Wellcome-MRC Stem Cell institute and Department of Neurology, Addenbrooke's Hospital University of Cambridge Cambridge United Kingdom
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26
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Fellner L, Gabassi E, Haybaeck J, Edenhofer F. Autophagy in α-Synucleinopathies-An Overstrained System. Cells 2021; 10:3143. [PMID: 34831366 PMCID: PMC8618716 DOI: 10.3390/cells10113143] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 11/05/2021] [Accepted: 11/08/2021] [Indexed: 01/01/2023] Open
Abstract
Alpha-synucleinopathies comprise progressive neurodegenerative diseases, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). They all exhibit the same pathological hallmark, which is the formation of α-synuclein positive deposits in neuronal or glial cells. The aggregation of α-synuclein in the cell body of neurons, giving rise to the so-called Lewy bodies (LBs), is the major characteristic for PD and DLB, whereas the accumulation of α-synuclein in oligodendroglial cells, so-called glial cytoplasmic inclusions (GCIs), is the hallmark for MSA. The mechanisms involved in the intracytoplasmic inclusion formation in neuronal and oligodendroglial cells are not fully understood to date. A possible mechanism could be an impaired autophagic machinery that cannot cope with the high intracellular amount of α-synuclein. In fact, different studies showed that reduced autophagy is involved in α-synuclein aggregation. Furthermore, altered levels of different autophagy markers were reported in PD, DLB, and MSA brains. To date, the trigger point in disease initiation is not entirely clear; that is, whether autophagy dysfunction alone suffices to increase α-synuclein or whether α-synuclein is the pathogenic driver. In the current review, we discuss the involvement of defective autophagy machinery in the formation of α-synuclein aggregates, propagation of α-synuclein, and the resulting neurodegenerative processes in α-synucleinopathies.
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Affiliation(s)
- Lisa Fellner
- Department of Genomics, Stem Cell Biology and Regenerative Medicine, Institute of Molecular Biology & CMBI, Leopold-Franzens-University Innsbruck, 6020 Innsbruck, Austria
| | - Elisa Gabassi
- Department of Genomics, Stem Cell Biology and Regenerative Medicine, Institute of Molecular Biology & CMBI, Leopold-Franzens-University Innsbruck, 6020 Innsbruck, Austria
| | - Johannes Haybaeck
- Institute of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Diagnostic & Research Center for Molecular Biomedicine, Institute of Pathology, Medical University of Graz, 8036 Graz, Austria
| | - Frank Edenhofer
- Department of Genomics, Stem Cell Biology and Regenerative Medicine, Institute of Molecular Biology & CMBI, Leopold-Franzens-University Innsbruck, 6020 Innsbruck, Austria
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27
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Sun Y, Long H, Xia W, Wang K, Zhang X, Sun B, Cao Q, Zhang Y, Dai B, Li D, Liu C. The hereditary mutation G51D unlocks a distinct fibril strain transmissible to wild-type α-synuclein. Nat Commun 2021; 12:6252. [PMID: 34716315 PMCID: PMC8556266 DOI: 10.1038/s41467-021-26433-2] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 10/07/2021] [Indexed: 11/21/2022] Open
Abstract
α-Synuclein (α-Syn) can form different fibril strains with distinct polymorphs and neuropathologies, which is associated with the clinicopathological variability in synucleinopathies. How different α-syn fibril strains are produced and selected under disease conditions remains poorly understood. In this study, we show that the hereditary mutation G51D induces α-syn to form a distinct fibril strain in vitro. The cryogenic electron microscopy (cryo-EM) structure of the G51D fibril strain was determined at 2.96 Å resolution. The G51D fibril displays a relatively small and extended serpentine fold distinct from other α-syn fibril structures. Moreover, we show by cryo-EM that wild-type (WT) α-syn can assembly into the G51D fibril strain via cross-seeding with G51D fibrils. Our study reveals a distinct structure of G51D fibril strain triggered by G51D mutation but feasibly adopted by both WT and G51D α-syn, which suggests the cross-seeding and strain selection of WT and mutant α-syn in familial Parkinson's disease (fPD).
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Affiliation(s)
- Yunpeng Sun
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 201210, Shanghai, China
- University of Chinese Academy of Sciences, 100049, Beijing, China
| | - Houfang Long
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 201210, Shanghai, China
- University of Chinese Academy of Sciences, 100049, Beijing, China
| | - Wencheng Xia
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 201210, Shanghai, China
- University of Chinese Academy of Sciences, 100049, Beijing, China
| | - Kun Wang
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 201210, Shanghai, China
- University of Chinese Academy of Sciences, 100049, Beijing, China
| | - Xia Zhang
- School of Life Science and Technology, ShanghaiTech University, 201210, Shanghai, China
| | - Bo Sun
- School of Life Science and Technology, ShanghaiTech University, 201210, Shanghai, China
| | - Qin Cao
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, 200030, Shanghai, China
| | - Yaoyang Zhang
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 201210, Shanghai, China
- University of Chinese Academy of Sciences, 100049, Beijing, China
| | - Bin Dai
- Institute of Nano Biomedicine and Engineering, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, 200210, Shanghai, China
| | - Dan Li
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, 200030, Shanghai, China
| | - Cong Liu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 201210, Shanghai, China.
- University of Chinese Academy of Sciences, 100049, Beijing, China.
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28
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Shan FY, Fung KM, Zieneldien T, Kim J, Cao C, Huang JH. Examining the Toxicity of α-Synuclein in Neurodegenerative Disorders. Life (Basel) 2021; 11:life11111126. [PMID: 34833002 PMCID: PMC8621244 DOI: 10.3390/life11111126] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/14/2021] [Accepted: 10/19/2021] [Indexed: 12/20/2022] Open
Abstract
Simple Summary Neurodegenerative disorders are complex disorders that display a variety of clinical manifestations. The second-most common neurodegenerative disorder is Parkinson’s disease, and the leading pathological protein of the disorder is considered to be α-synuclein. Nonetheless, α-synuclein accumulation also seems to result in multiple system atrophy and dementia with Lewy bodies. In order to obtain a more proficient understanding in the pathological progression of these synucleinopathies, it is crucial to observe the post-translational modifications of α-synuclein and the conformations of α-synuclein, as well as its role in the dysfunction of cellular pathways. Abstract α-synuclein is considered the main pathological protein in a variety of neurodegenerative disorders, such as Parkinson’s disease, multiple system atrophy, and dementia with Lewy bodies. As of now, numerous studies have been aimed at examining the post-translational modifications of α-synuclein to determine their effects on α-synuclein aggregation, propagation, and oligomerization, as well as the potential cellular pathway dysfunctions caused by α-synuclein, to determine the role of the protein in disease progression. Furthermore, α-synuclein also appears to contribute to the fibrilization of tau and amyloid beta, which are crucial proteins in Alzheimer’s disease, advocating for α-synuclein’s preeminent role in neurodegeneration. Due to this, investigating the mechanisms of toxicity of α-synuclein in neurodegeneration may lead to a more proficient understanding of the timeline progression in neurodegenerative synucleinopathies and could thereby lead to the development of potent targeted therapies.
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Affiliation(s)
- Frank Y. Shan
- Department of Anatomic Pathology, Baylor Scott & White Medical Center, College of Medicine, Texas A&M University, Temple, TX 76508, USA
- Correspondence: (F.Y.S.); (T.Z.)
| | - Kar-Ming Fung
- Department of Pathology, University of Oklahoma Medical Center, University of Oklahoma, Norman, OK 73019, USA;
| | - Tarek Zieneldien
- Department of Pharmaceutical Sciences, Taneja College of Pharmacy, University of South Florida, Tampa, FL 33620, USA; (J.K.); (C.C.)
- Correspondence: (F.Y.S.); (T.Z.)
| | - Janice Kim
- Department of Pharmaceutical Sciences, Taneja College of Pharmacy, University of South Florida, Tampa, FL 33620, USA; (J.K.); (C.C.)
| | - Chuanhai Cao
- Department of Pharmaceutical Sciences, Taneja College of Pharmacy, University of South Florida, Tampa, FL 33620, USA; (J.K.); (C.C.)
| | - Jason H. Huang
- Department of Neurosurgery, Baylor Scott & White Medical Center, College of Medicine, Texas A&M University, Temple, TX 76508, USA;
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Marmion DJ, Peelaerts W, Kordower JH. A historical review of multiple system atrophy with a critical appraisal of cellular and animal models. J Neural Transm (Vienna) 2021; 128:1507-1527. [PMID: 34613484 PMCID: PMC8528759 DOI: 10.1007/s00702-021-02419-8] [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: 07/06/2021] [Accepted: 09/15/2021] [Indexed: 12/31/2022]
Abstract
Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA), and dysautonomia with cerebellar ataxia or parkinsonian motor features. Isolated autonomic dysfunction with predominant genitourinary dysfunction and orthostatic hypotension and REM sleep behavior disorder are common characteristics of a prodromal phase, which may occur years prior to motor-symptom onset. MSA is a unique synucleinopathy, in which alpha-synuclein (aSyn) accumulates and forms insoluble inclusions in the cytoplasm of oligodendrocytes, termed glial cytoplasmic inclusions (GCIs). The origin of, and precise mechanism by which aSyn accumulates in MSA are unknown, and, therefore, disease-modifying therapies to halt or slow the progression of MSA are currently unavailable. For these reasons, much focus in the field is concerned with deciphering the complex neuropathological mechanisms by which MSA begins and progresses through the course of the disease. This review focuses on the history, etiopathogenesis, neuropathology, as well as cell and animal models of MSA.
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Affiliation(s)
- David J Marmion
- Parkinson's Disease Research Unit, Department of Neurobiology, Barrow Neurological Institute, Phoenix, AZ, USA
| | - Wouter Peelaerts
- Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven Brain Institute, KU Leuven, Leuven, Belgium
| | - Jeffrey H Kordower
- ASU-Banner Neurodegenerative Disease Research Center, Biodesign Institute, Arizona State University, Tempe, AZ, USA.
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Jellinger KA, Wenning GK, Stefanova N. Is Multiple System Atrophy a Prion-like Disorder? Int J Mol Sci 2021; 22:10093. [PMID: 34576255 PMCID: PMC8472631 DOI: 10.3390/ijms221810093] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 09/16/2021] [Accepted: 09/16/2021] [Indexed: 02/08/2023] Open
Abstract
Multiple system atrophy (MSA) is a rapidly progressive, fatal neurodegenerative disease of uncertain aetiology that belongs to the family of α-synucleinopathies. It clinically presents with parkinsonism, cerebellar, autonomic, and motor impairment in variable combinations. Pathological hallmarks are fibrillary α-synuclein (αSyn)-rich glial cytoplasmic inclusions (GCIs) mainly involving oligodendroglia and to a lesser extent neurons, inducing a multisystem neurodegeneration, glial activation, and widespread demyelinization. The neuronal αSyn pathology of MSA has molecular properties different from Lewy bodies in Parkinson's disease (PD), both of which could serve as a pool of αSyn (prion) seeds that could initiate and drive the pathogenesis of synucleinopathies. The molecular cascade leading to the "prion-like" transfer of "strains" of aggregated αSyn contributing to the progression of the disease is poorly understood, while some presented evidence that MSA is a prion disease. However, this hypothesis is difficult to reconcile with postmortem analysis of human brains and the fact that MSA-like pathology was induced by intracerebral inoculation of human MSA brain homogenates only in homozygous mutant 53T mice, without production of disease-specific GCIs, or with replication of MSA prions in primary astrocyte cultures from transgenic mice expressing human αSyn. Whereas recent intrastriatal injection of Lewy body-derived or synthetic human αSyn fibrils induced PD-like pathology including neuronal αSyn aggregates in macaques, no such transmission of αSyn pathology in non-human primates by MSA brain lysate has been reported until now. Given the similarities between αSyn and prions, there is a considerable debate whether they should be referred to as "prions", "prion-like", "prionoids", or something else. Here, the findings supporting the proposed nature of αSyn as a prion and its self-propagation through seeding as well as the transmissibility of neurodegenerative disorders are discussed. The proof of disease causation rests on the concordance of scientific evidence, none of which has provided convincing evidence for the classification of MSA as a prion disease or its human transmission until now.
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Affiliation(s)
| | - Gregor K. Wenning
- Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, 6020 Innsbruck, Austria; (G.K.W.); (N.S.)
| | - Nadia Stefanova
- Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, 6020 Innsbruck, Austria; (G.K.W.); (N.S.)
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Valek L, Tegeder I. Failure of Diphtheria Toxin Model to Induce Parkinson-Like Behavior in Mice. Int J Mol Sci 2021; 22:ijms22179496. [PMID: 34502404 PMCID: PMC8430633 DOI: 10.3390/ijms22179496] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/12/2021] [Accepted: 08/29/2021] [Indexed: 12/21/2022] Open
Abstract
Rodent models of Parkinson’s disease are based on transgenic expression of mutant synuclein, deletion of PD genes, injections of MPTP or rotenone, or seeding of synuclein fibrils. The models show histopathologic features of PD such as Lewi bodies but mostly only subtle in vivo manifestations or systemic toxicity. The models only partly mimic a predominant loss of dopaminergic neurons in the substantia nigra. We therefore generated mice that express the transgenic diphtheria toxin receptor (DTR) specifically in DA neurons by crossing DAT-Cre mice with Rosa26 loxP-STOP-loxP DTR mice. After defining a well-tolerated DTx dose, DAT-DTR and DTR-flfl controls were subjected to non-toxic DTx treatment (5 × 100 pg/g) and subsequent histology and behavioral tests. DAT protein levels were reduced in the midbrain, and tyrosine hydroxylase-positive neurons were reduced in the substantia nigra, whereas the pan-neuronal marker NeuN was not affected. Despite the promising histologic results, there was no difference in motor function tests or open field behavior. These are tests in which double mutant Pink1−/−SNCAA53T Parkinson mice show behavioral abnormalities. Higher doses of DTx were toxic in both groups. The data suggest that DTx treatment in mice with Cre/loxP-driven DAT-DTR expression leads to partial ablation of DA-neurons but without PD-reminiscent behavioral correlates.
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Hoppe SO, Uzunoğlu G, Nussbaum-Krammer C. α-Synuclein Strains: Does Amyloid Conformation Explain the Heterogeneity of Synucleinopathies? Biomolecules 2021; 11:931. [PMID: 34201558 PMCID: PMC8301881 DOI: 10.3390/biom11070931] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 06/15/2021] [Accepted: 06/19/2021] [Indexed: 12/17/2022] Open
Abstract
Synucleinopathies are a heterogeneous group of neurodegenerative diseases with amyloid deposits that contain the α-synuclein (SNCA/α-Syn) protein as a common hallmark. It is astonishing that aggregates of a single protein are able to give rise to a whole range of different disease manifestations. The prion strain hypothesis offers a possible explanation for this conundrum. According to this hypothesis, a single protein sequence is able to misfold into distinct amyloid structures that can cause different pathologies. In fact, a growing body of evidence suggests that conformationally distinct α-Syn assemblies might be the causative agents behind different synucleinopathies. In this review, we provide an overview of research on the strain hypothesis as it applies to synucleinopathies and discuss the potential implications for diagnostic and therapeutic purposes.
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Affiliation(s)
| | | | - Carmen Nussbaum-Krammer
- Center for Molecular Biology, Heidelberg University (ZMBH) and German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, D-69120 Heidelberg, Germany; (S.O.H.); (G.U.)
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Guo S, Zhao B, An Y, Zhang Y, Meng Z, Zhou Y, Zheng M, Yang D, Wang M, Ying B. Potential Fluid Biomarkers and a Prediction Model for Better Recognition Between Multiple System Atrophy-Cerebellar Type and Spinocerebellar Ataxia. Front Aging Neurosci 2021; 13:644699. [PMID: 33958996 PMCID: PMC8093568 DOI: 10.3389/fnagi.2021.644699] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 03/12/2021] [Indexed: 02/05/2023] Open
Abstract
Objective This study screened potential fluid biomarkers and developed a prediction model based on the easily obtained information at initial inspection to identify ataxia patients more likely to have multiple system atrophy-cerebellar type (MSA-C). Methods We established a retrospective cohort with 125 ataxia patients from southwest China between April 2018 and June 2020. Demographic and laboratory variables obtained at the time of hospital admission were screened using Least Absolute Shrinkage and Selection Operator (LASSO) regression and logistic regression to construct a diagnosis score. The receiver operating characteristic (ROC) and decision curve analyses were performed to assess the accuracy and net benefit of the model. Also, independent validation using 25 additional ataxia patients was carried out to verify the model efficiency. Then the model was translated into a visual and operable web application using the R studio and Shiny package. Results From 47 indicators, five variables were selected and integrated into the prediction model, including the age of onset (AO), direct bilirubin (DBIL), aspartate aminotransferase (AST), eGFR, and synuclein-alpha. The prediction model exhibited an area under the curve (AUC) of 0.929 for the training cohort and an AUC of 0.917 for the testing cohort. The decision curve analysis (DCA) plot displayed a good net benefit for this model, and external validation confirmed its reliability. The model also was translated into a web application that is freely available to the public. Conclusion The prediction model that was developed based on laboratory and demographic variables obtained from ataxia patients at admission to the hospital might help improve the ability to differentiate MSA-C from spinocerebellar ataxia clinically.
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Affiliation(s)
- Shuo Guo
- Department of Laboratory Medicine, West China Hospital of Sichuan University, Chengdu, China
| | - Bi Zhao
- Department of Neurology, West China Hospital of Sichuan University, Chengdu, China
| | - Yunfei An
- Department of Laboratory Medicine, West China Hospital of Sichuan University, Chengdu, China
| | - Yu Zhang
- Department of Neurology, West China Hospital of Sichuan University, Chengdu, China
| | - Zirui Meng
- Department of Laboratory Medicine, West China Hospital of Sichuan University, Chengdu, China
| | - Yanbing Zhou
- Department of Laboratory Medicine, West China Hospital of Sichuan University, Chengdu, China
| | - Mingxue Zheng
- Department of Laboratory Medicine, West China Hospital of Sichuan University, Chengdu, China
| | - Dan Yang
- Department of Radiology, West China Hospital of Sichuan University, Chengdu, China
| | - Minjin Wang
- Department of Laboratory Medicine, West China Hospital of Sichuan University, Chengdu, China
| | - Binwu Ying
- Department of Laboratory Medicine, West China Hospital of Sichuan University, Chengdu, China
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Retina as a Model to Study In Vivo Transmission of α-Synuclein in the A53T Mouse Model of Parkinson's Disease. Methods Mol Biol 2021; 2224:75-85. [PMID: 33606207 DOI: 10.1007/978-1-0716-1008-4_5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Parkinson's disease is a neurodegenerative disorder characterized by accumulation of misfolded α-synuclein within the central nervous system (CNS). Retinal manifestations have been widely described as a prodromal symptom; however, we have a limited understanding of the retinal pathology associated with Parkinson's disease. The strong similarities between the retina and the brain and the accessibility of the retina has potentiated studies to investigate retinal pathology in an effort to identify biomarkers for early detection, as well as for monitoring the progression of disease and efficacy of therapies as they become available. Here, we discuss a study conducted using a transgenic mouse model of Parkinson's disease (TgM83, expressing human α-synuclein containing the familial PD-associated A53T mutation) to demonstrate the effect of the A53T α-synuclein mutation on the retina. Additionally, we show that "seeding" with brain homogenates from clinically ill TgM83 mice accelerates the accumulation of retinal α-synuclein. The work described in this chapter provides insight into retinal changes associated with Parkinson's disease and identifies retinal indicators of Parkinson's disease pathogenesis that could serve as potential biomarkers for early detection.
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MicroRNAs Regulating Autophagy in Neurodegeneration. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1208:191-264. [PMID: 34260028 DOI: 10.1007/978-981-16-2830-6_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Social and economic impacts of neurodegenerative diseases (NDs) become more prominent in our constantly aging population. Currently, due to the lack of knowledge about the aetiology of most NDs, only symptomatic treatment is available for patients. Hence, researchers and clinicians are in need of solid studies on pathological mechanisms of NDs. Autophagy promotes degradation of pathogenic proteins in NDs, while microRNAs post-transcriptionally regulate multiple signalling networks including autophagy. This chapter will critically discuss current research advancements in the area of microRNAs regulating autophagy in NDs. Moreover, we will introduce basic strategies and techniques used in microRNA research. Delineation of the mechanisms contributing to NDs will result in development of better approaches for their early diagnosis and effective treatment.
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Jeon YM, Kwon Y, Jo M, Lee S, Kim S, Kim HJ. The Role of Glial Mitochondria in α-Synuclein Toxicity. Front Cell Dev Biol 2020; 8:548283. [PMID: 33262983 PMCID: PMC7686475 DOI: 10.3389/fcell.2020.548283] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 10/20/2020] [Indexed: 12/18/2022] Open
Abstract
The abnormal accumulation of alpha-synuclein (α-syn) aggregates in neurons and glial cells is widely known to be associated with many neurodegenerative diseases, including Parkinson's disease (PD), Dementia with Lewy bodies (DLB), and Multiple system atrophy (MSA). Mitochondrial dysfunction in neurons and glia is known as a key feature of α-syn toxicity. Studies aimed at understanding α-syn-induced toxicity and its role in neurodegenerative diseases have primarily focused on neurons. However, a growing body of evidence demonstrates that glial cells such as microglia and astrocytes have been implicated in the initial pathogenesis and the progression of α-Synucleinopathy. Glial cells are important for supporting neuronal survival, synaptic functions, and local immunity. Furthermore, recent studies highlight the role of mitochondrial metabolism in the normal function of glial cells. In this work, we review the complex relationship between glial mitochondria and α-syn-mediated neurodegeneration, which may provide novel insights into the roles of glial cells in α-syn-associated neurodegenerative diseases.
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Affiliation(s)
- Yu-Mi Jeon
- Dementia Research Group, Korea Brain Research Institute, Daegu, South Korea
| | - Younghwi Kwon
- Dementia Research Group, Korea Brain Research Institute, Daegu, South Korea
- Department of Brain and Cognitive Sciences, DGIST, Daegu, South Korea
| | - Myungjin Jo
- Dementia Research Group, Korea Brain Research Institute, Daegu, South Korea
| | - Shinrye Lee
- Dementia Research Group, Korea Brain Research Institute, Daegu, South Korea
| | - Seyeon Kim
- Dementia Research Group, Korea Brain Research Institute, Daegu, South Korea
- Department of Brain and Cognitive Sciences, DGIST, Daegu, South Korea
| | - Hyung-Jun Kim
- Dementia Research Group, Korea Brain Research Institute, Daegu, South Korea
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Del Rio JA, Ferrer I. Potential of Microfluidics and Lab-on-Chip Platforms to Improve Understanding of " prion-like" Protein Assembly and Behavior. Front Bioeng Biotechnol 2020; 8:570692. [PMID: 33015021 PMCID: PMC7506036 DOI: 10.3389/fbioe.2020.570692] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 08/18/2020] [Indexed: 12/14/2022] Open
Abstract
Human aging is accompanied by a relevant increase in age-associated chronic pathologies, including neurodegenerative and metabolic diseases. The appearance and evolution of numerous neurodegenerative diseases is paralleled by the appearance of intracellular and extracellular accumulation of misfolded proteins in affected brains. In addition, recent evidence suggests that most of these amyloid proteins can behave and propagate among neural cells similarly to infective prions. In order to improve understanding of the seeding and spreading processes of these "prion-like" amyloids, microfluidics and 3D lab-on-chip approaches have been developed as highly valuable tools. These techniques allow us to monitor changes in cellular and molecular processes responsible for amyloid seeding and cell spreading and their parallel effects in neural physiology. Their compatibility with new optical and biochemical techniques and their relative availability have increased interest in them and in their use in numerous laboratories. In addition, recent advances in stem cell research in combination with microfluidic platforms have opened new humanized in vitro models for myriad neurodegenerative diseases affecting different cellular targets of the vascular, muscular, and nervous systems, and glial cells. These new platforms help reduce the use of animal experimentation. They are more reproducible and represent a potential alternative to classical approaches to understanding neurodegeneration. In this review, we summarize recent progress in neurobiological research in "prion-like" protein using microfluidic and 3D lab-on-chip approaches. These approaches are driven by various fields, including chemistry, biochemistry, and cell biology, and they serve to facilitate the development of more precise human brain models for basic mechanistic studies of cell-to-cell interactions and drug discovery.
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Affiliation(s)
- Jose A Del Rio
- Molecular and Cellular Neurobiotechnology, Institute for Bioengineering of Catalonia, Barcelona Institute of Science and Technology, Barcelona, Spain.,Department of Cell Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, Barcelona, Spain.,Center for Networked Biomedical Research on Neurodegenerative Diseases (Ciberned), Barcelona, Spain.,Institute of Neuroscience, University of Barcelona, Barcelona, Spain
| | - Isidre Ferrer
- Center for Networked Biomedical Research on Neurodegenerative Diseases (Ciberned), Barcelona, Spain.,Institute of Neuroscience, University of Barcelona, Barcelona, Spain.,Department of Pathology and Experimental Therapeutics, University of Barcelona, Barcelona, Spain.,Bellvitge University Hospital, Hospitalet de Llobregat, Barcelona, Spain.,Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain
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Zhao K, Lim YJ, Liu Z, Long H, Sun Y, Hu JJ, Zhao C, Tao Y, Zhang X, Li D, Li YM, Liu C. Parkinson's disease-related phosphorylation at Tyr39 rearranges α-synuclein amyloid fibril structure revealed by cryo-EM. Proc Natl Acad Sci U S A 2020; 117:20305-20315. [PMID: 32737160 PMCID: PMC7443891 DOI: 10.1073/pnas.1922741117] [Citation(s) in RCA: 125] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Posttranslational modifications (PTMs) of α-synuclein (α-syn), e.g., phosphorylation, play an important role in modulating α-syn pathology in Parkinson's disease (PD) and α-synucleinopathies. Accumulation of phosphorylated α-syn fibrils in Lewy bodies and Lewy neurites is the histological hallmark of these diseases. However, it is unclear how phosphorylation relates to α-syn pathology. Here, by combining chemical synthesis and bacterial expression, we obtained homogeneous α-syn fibrils with site-specific phosphorylation at Y39, which exhibits enhanced neuronal pathology in rat primary cortical neurons. We determined the cryo-electron microscopy (cryo-EM) structure of the pY39 α-syn fibril, which reveals a fold of α-syn with pY39 in the center of the fibril core forming an electrostatic interaction network with eight charged residues in the N-terminal region of α-syn. This structure composed of residues 1 to 100 represents the largest α-syn fibril core determined so far. This work provides structural understanding on the pathology of the pY39 α-syn fibril and highlights the importance of PTMs in defining the polymorphism and pathology of amyloid fibrils in neurodegenerative diseases.
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Affiliation(s)
- Kun Zhao
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China
- University of Chinese Academy of Sciences, 100049 Beijing, China
| | - Yeh-Jun Lim
- Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, 100084 Beijing, China
| | - Zhenying Liu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China
- University of Chinese Academy of Sciences, 100049 Beijing, China
| | - Houfang Long
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China
- University of Chinese Academy of Sciences, 100049 Beijing, China
| | - Yunpeng Sun
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China
- University of Chinese Academy of Sciences, 100049 Beijing, China
| | - Jin-Jian Hu
- Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, 100084 Beijing, China
| | - Chunyu Zhao
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China
- University of Chinese Academy of Sciences, 100049 Beijing, China
| | - Youqi Tao
- Bio-X Institutes, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Xing Zhang
- Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310058 Hangzhou, China
- Department of Biophysics, Zhejiang University School of Medicine, 310058 Hangzhou, China
- Center of Cryo-Electron Microscopy, Zhejiang University School of Medicine, 310058 Hangzhou, China
| | - Dan Li
- Bio-X Institutes, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Yan-Mei Li
- Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, 100084 Beijing, China;
| | - Cong Liu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China;
- University of Chinese Academy of Sciences, 100049 Beijing, China
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Presence of intrinsically disordered proteins can inhibit the nucleation phase of amyloid fibril formation of Aβ(1-42) in amino acid sequence independent manner. Sci Rep 2020; 10:12334. [PMID: 32703978 PMCID: PMC7378830 DOI: 10.1038/s41598-020-69129-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 06/19/2020] [Indexed: 11/27/2022] Open
Abstract
The molecular shield effect was studied for intrinsically disordered proteins (IDPs) that do not adopt compact and stable protein folds. IDPs are found among many stress-responsive gene products and cryoprotective- and drought-protective proteins. We recently reported that some fragments of human genome-derived IDPs are cryoprotective for cellular enzymes, despite a lack of relevant amino acid sequence motifs. This sequence-independent IDP function may reflect their molecular shield effect. This study examined the inhibitory activity of IDPs against fibril formation in an amyloid beta peptide (Aβ(1–42)) model system. Four of five human genome-derived IDPs (size range 20 to 44 amino acids) showed concentration-dependent inhibition of amyloid formation (IC50 range between 60 and 130 μM against 20 μM Aβ(1–42)). The IC50 value was two orders of magnitude lower than that of polyethylene-glycol and dextran, used as neutral hydrophilic polymer controls. Nuclear magnetic resonance with 15 N-labeled Aβ(1–42) revealed no relevant molecular interactions between Aβ(1–42) and IDPs. The inhibitory activities were abolished by adding external amyloid-formation seeds. Therefore, IDPs seemed to act only at the amyloid nucleation phase but not at the elongation phase. These results suggest that IDPs (0.1 mM or less) have a molecular shield effect that prevents aggregation of susceptible molecules.
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Pérez-Soriano A, Bravo P, Soto M, Infante J, Fernández M, Valldeoriola F, Muñoz E, Compta Y, Tolosa E, Garrido A, Ezquerra M, Fernández-Santiago R, Martí MJ. MicroRNA Deregulation in Blood Serum Identifies Multiple System Atrophy Altered Pathways. Mov Disord 2020; 35:1873-1879. [PMID: 32687224 DOI: 10.1002/mds.28143] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 05/16/2020] [Accepted: 05/20/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND OBJECTIVES MicroRNA (miRNA) changes are observed in PD but remain poorly explored in other α-synucleinopathies such as MSA. METHODS By genome-wide analysis we profiled microRNA expression in serum from 20 MSA cases compared to 40 controls. By qPCR we validated top differentially expressed microRNAs in another sample of 20 MSA and 20 controls. We also assessed the expression of MSA differentially expressed microRNAs in two consecutive sets of 19 and 18 PD patients. RESULTS In the discovery set we identified 25 differentially expressed microRNAs associated with MSA, which are related to prion disease, fatty acid metabolism, and Notch signaling. Among these, we selected nine differentially expressed microRNAs and by qPCR confirmed array findings in a second MSA sample. MicroRNA-7641 and microRNA-191 consistently differentiated between MSA and PD. CONCLUSIONS Serum microRNA changes occur in MSA and may reflect disease-associated mechanisms. We identified two microRNAs which may differentiate MSA from PD. © 2020 International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Alexandra Pérez-Soriano
- Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders: Clinical and Experimental Research; Department of Neurology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED: CB06/05/0018-ISCIII) Barcelona, Spain.,Parkinson's disease & Movement Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, ERN-RND, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Paloma Bravo
- Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders: Clinical and Experimental Research; Department of Neurology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain
| | - Marta Soto
- Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders: Clinical and Experimental Research; Department of Neurology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain
| | - Jon Infante
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED: CB06/05/0018-ISCIII) Barcelona, Spain.,Movement Disorders Unit, Department of Neurology, Hospital Universitario Marqués de Valdecilla, Universidad de Cantabria, Santander, Spain
| | - Manel Fernández
- Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders: Clinical and Experimental Research; Department of Neurology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED: CB06/05/0018-ISCIII) Barcelona, Spain.,Parkison's disease and Movement Disorders group of the Institut de Neurociènices (Universitat de Barcelona), Barcelona, Spain
| | - Francesc Valldeoriola
- Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders: Clinical and Experimental Research; Department of Neurology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED: CB06/05/0018-ISCIII) Barcelona, Spain.,Parkinson's disease & Movement Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, ERN-RND, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Esteban Muñoz
- Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders: Clinical and Experimental Research; Department of Neurology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED: CB06/05/0018-ISCIII) Barcelona, Spain.,Parkinson's disease & Movement Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, ERN-RND, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Yaroslau Compta
- Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders: Clinical and Experimental Research; Department of Neurology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED: CB06/05/0018-ISCIII) Barcelona, Spain.,Parkinson's disease & Movement Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, ERN-RND, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Eduard Tolosa
- Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders: Clinical and Experimental Research; Department of Neurology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED: CB06/05/0018-ISCIII) Barcelona, Spain.,Parkinson's disease & Movement Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, ERN-RND, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Alicia Garrido
- Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders: Clinical and Experimental Research; Department of Neurology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED: CB06/05/0018-ISCIII) Barcelona, Spain.,Parkinson's disease & Movement Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, ERN-RND, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Mario Ezquerra
- Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders: Clinical and Experimental Research; Department of Neurology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED: CB06/05/0018-ISCIII) Barcelona, Spain
| | - Rubén Fernández-Santiago
- Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders: Clinical and Experimental Research; Department of Neurology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED: CB06/05/0018-ISCIII) Barcelona, Spain
| | - María-José Martí
- Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders: Clinical and Experimental Research; Department of Neurology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED: CB06/05/0018-ISCIII) Barcelona, Spain.,Parkinson's disease & Movement Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, ERN-RND, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
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Yue T, Lu H, Yao XM, Du X, Wang LL, Guo DD, Liu YM. Elevated serum growth differentiation factor 15 in multiple system atrophy patients: A case control study. World J Clin Cases 2020; 8:2473-2483. [PMID: 32607324 PMCID: PMC7322433 DOI: 10.12998/wjcc.v8.i12.2473] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 05/09/2020] [Accepted: 05/12/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Multiple system atrophy (MSA) is a serious progressive neurodegenerative disease. Early diagnosis of MSA is very difficult, and diagnostic biomarkers are limited. Growth differentiation factor 15 (GDF15) is involved in the differentiation and progression of the central nervous system, and is widely distributed in peripheral blood, which may be a novel biomarker for MSA.
AIM To determine serum GDF15 levels, related factors and their potential diagnostic value in MSA patients, compared with Parkinson’s disease (PD) patients and healthy controls.
METHODS A case-control study was conducted, including 49 MSA patients, 50 PD patients and 50 healthy controls. Serum GDF15 levels were measured by human enzyme-linked immunosorbent assay, and the differences between the MSA, PD and control groups were analyzed. Further investigations were performed in different MSA subgroups according to age of onset, sex, clinical subtypes, diagnostic criteria, and disease duration. Receiver-operating characteristic curve analysis was used to evaluate the diagnostic value of GDF15, especially for the differential diagnosis between MSA and PD.
RESULTS Serum GDF15 levels were significantly higher in MSA patients than in PD patients and healthy controls (P = 0.000). Males and those with a disease duration of more than three years showed higher serum GDF15 levels (P = 0.043 and 0.000; respectively). Serum GDF15 levels may be a potential diagnostic biomarker for MSA patients compared with healthy controls and PD patients (cutoff: 470.42 pg/mL, sensitivity: 85.7%, specificity: 88.0%; cutoff: 1075.91 pg/mL, sensitivity: 51.0%, specificity: 96.0%; respectively).
CONCLUSION Serum GDF15 levels are significantly higher in MSA patients and provide suggestions on the etiology of MSA.
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Affiliation(s)
- Tao Yue
- Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
- Department of Gerontology, Zibo Central Hospital, Zibo 255036, Shandong Province, China
| | - Hui Lu
- Department of Ophthalmology, Zibo Central Hospital, Zibo 255036, Shandong Province, China
| | - Xiao-Mei Yao
- Department of Gerontology, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250013, Shandong Province, China
| | - Xia Du
- Department of Neurology, Jinan Central Hospital Affiliated to Shandong University, Jinan 250013, Shandong Province, China
| | - Ling-Ling Wang
- Department of Neurology, Yantaishan Hospital, Yantai 264001, Shandong Province, China
| | - Dan-Dan Guo
- Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
| | - Yi-Ming Liu
- Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
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Zhao K, Li Y, Liu Z, Long H, Zhao C, Luo F, Sun Y, Tao Y, Su XD, Li D, Li X, Liu C. Parkinson's disease associated mutation E46K of α-synuclein triggers the formation of a distinct fibril structure. Nat Commun 2020; 11:2643. [PMID: 32457390 PMCID: PMC7250837 DOI: 10.1038/s41467-020-16386-3] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 04/28/2020] [Indexed: 01/20/2023] Open
Abstract
Amyloid aggregation of α-synuclein (α-syn) is closely associated with Parkinson's disease (PD) and other synucleinopathies. Several single amino-acid mutations (e.g. E46K) of α-syn have been identified causative to the early onset of familial PD. Here, we report the cryo-EM structure of an α-syn fibril formed by N-terminally acetylated E46K mutant α-syn (Ac-E46K). The fibril structure represents a distinct fold of α-syn, which demonstrates that the E46K mutation breaks the electrostatic interactions in the wild type (WT) α-syn fibril and thus triggers the rearrangement of the overall structure. Furthermore, we show that the Ac-E46K fibril is less resistant to harsh conditions and protease cleavage, and more prone to be fragmented with an enhanced seeding capability than that of the WT fibril. Our work provides a structural view to the severe pathology of the PD familial mutation E46K of α-syn and highlights the importance of electrostatic interactions in defining the fibril polymorphs.
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Affiliation(s)
- Kun Zhao
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yaowang Li
- Key Laboratory of Protein Sciences (Tsinghua University), Ministry of Education, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Zhenying Liu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Houfang Long
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Chunyu Zhao
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Feng Luo
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yunpeng Sun
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Youqi Tao
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, 200030, China
| | - Xiao-Dong Su
- State Key Laboratory of Protein and Plant Gene Research, and Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Peking University, Beijing, 100871, China
| | - Dan Li
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, 200030, China.
- Bio-X-Renji Hospital Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China.
| | - Xueming Li
- Key Laboratory of Protein Sciences (Tsinghua University), Ministry of Education, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
| | - Cong Liu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
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Sorrentino ZA, Giasson BI. The emerging role of α-synuclein truncation in aggregation and disease. J Biol Chem 2020; 295:10224-10244. [PMID: 32424039 DOI: 10.1074/jbc.rev120.011743] [Citation(s) in RCA: 120] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 05/13/2020] [Indexed: 12/21/2022] Open
Abstract
α-Synuclein (αsyn) is an abundant brain neuronal protein that can misfold and polymerize to form toxic fibrils coalescing into pathologic inclusions in neurodegenerative diseases, including Parkinson's disease, Lewy body dementia, and multiple system atrophy. These fibrils may induce further αsyn misfolding and propagation of pathologic fibrils in a prion-like process. It is unclear why αsyn initially misfolds, but a growing body of literature suggests a critical role of partial proteolytic processing resulting in various truncations of the highly charged and flexible carboxyl-terminal region. This review aims to 1) summarize recent evidence that disease-specific proteolytic truncations of αsyn occur in Parkinson's disease, Lewy body dementia, and multiple system atrophy and animal disease models; 2) provide mechanistic insights on how truncation of the amino and carboxyl regions of αsyn may modulate the propensity of αsyn to pathologically misfold; 3) compare experiments evaluating the prion-like properties of truncated forms of αsyn in various models with implications for disease progression; 4) assess uniquely toxic properties imparted to αsyn upon truncation; and 5) discuss pathways through which truncated αsyn forms and therapies targeted to interrupt them. Cumulatively, it is evident that truncation of αsyn, particularly carboxyl truncation that can be augmented by dysfunctional proteostasis, dramatically potentiates the propensity of αsyn to pathologically misfold into uniquely toxic fibrils with modulated prion-like seeding activity. Therapeutic strategies and experimental paradigms should operate under the assumption that truncation of αsyn is likely occurring in both initial and progressive disease stages, and preventing truncation may be an effective preventative strategy against pathologic inclusion formation.
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Affiliation(s)
- Zachary A Sorrentino
- Department of Neuroscience, College of Medicine, University of Florida, Gainesville, Florida, USA.,Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Benoit I Giasson
- Department of Neuroscience, College of Medicine, University of Florida, Gainesville, Florida, USA .,Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, Florida, USA.,McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, Florida, USA
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Ding X, Zhou L, Jiang X, Liu H, Yao J, Zhang R, Liang D, Wang F, Ma M, Tang B, Wu E, Teng J, Wang X. Propagation of Pathological α-Synuclein from the Urogenital Tract to the Brain Initiates MSA-like Syndrome. iScience 2020; 23:101166. [PMID: 32470898 PMCID: PMC7260590 DOI: 10.1016/j.isci.2020.101166] [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: 07/17/2019] [Revised: 12/29/2019] [Accepted: 05/08/2020] [Indexed: 01/10/2023] Open
Abstract
The neuropathological feature of multiple system atrophy (MSA), a fatal adult-onset disorder without effective therapy, is the accumulation of pathological α-synuclein (α-Syn) in the central nervous system (CNS). Here we show that pathological α-Syn exists in nerve terminals in detrusor and external urethral sphincter (EUS) of patients with MSA. Furthermore, α-Syn-preformed fibrils (PFFs) injected in the EUS or detrusor in TgM83+/− mice initiated the transmission of pathological α-Syn from the urogenital tract to brain via micturition reflex pathways, and these mice developed widespread phosphorylated α-Syn inclusion pathology together with phenotypes. In addition, urinary dysfunction and denervation-reinnervation of external anal sphincter were detected earlier in the mouse models with α-Syn PFFs inoculation before the behavioral manifestations. These results suggest that pathological α-Syn spreading through the micturition reflex pathways retrogradely from the urogenital tract to CNS may lead to urinary dysfunction in patients with MSA, which is different from the etiology of idiopathic Parkinson disease.
Pathological α-Syn exhibits in nerve terminals in DET and EUS of patients with MSA Propagation of pathological α-Syn from urinary tract to CNS causes MSA-like syndrome The mouse models show urinary dysfunction and abnormal EAS EMG before motor deficits Lower urinary tract injection of α-Syn PFFs induces autonomic and motor dysfunctions
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Affiliation(s)
- Xuebing Ding
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Institute of Parkinson and Movement Disorder, Zhengzhou University, Zhengzhou, Henan 450052, China.
| | - Lebo Zhou
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Institute of Parkinson and Movement Disorder, Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Xiaoyi Jiang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Institute of Parkinson and Movement Disorder, Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Han Liu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Institute of Parkinson and Movement Disorder, Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Jing Yao
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Institute of Parkinson and Movement Disorder, Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Rui Zhang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Institute of Parkinson and Movement Disorder, Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Dongxiao Liang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Institute of Parkinson and Movement Disorder, Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Fengfei Wang
- Neuroscience Institute and Department of Neurosurgery, Baylor Scott & White Health, Temple, TX 76508, USA; College of Medicine, Texas A&M Health Science Center, College Station, TX 77843, USA
| | - Mingming Ma
- Department of Neurology, Affiliated People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, China.
| | - Beisha Tang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan 410008, China.
| | - Erxi Wu
- Neuroscience Institute and Department of Neurosurgery, Baylor Scott & White Health, Temple, TX 76508, USA; College of Medicine, Texas A&M Health Science Center, College Station, TX 77843, USA; College of Pharmacy, Texas A&M Health Science Center, College Station, TX 77843, USA; LIVESTRONG Cancer Institutes, Dell Medical School, the University of Texas at Austin, Austin, TX 78712, USA.
| | - Junfang Teng
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Institute of Parkinson and Movement Disorder, Zhengzhou University, Zhengzhou, Henan 450052, China.
| | - Xuejing Wang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Institute of Parkinson and Movement Disorder, Zhengzhou University, Zhengzhou, Henan 450052, China.
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Outeiro TF, Mestre TA. Synuclein Meeting 2019: where we are and where we need to go. J Neurochem 2020; 150:462-466. [PMID: 31441047 DOI: 10.1111/jnc.14825] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 07/09/2019] [Indexed: 01/01/2023]
Abstract
The Synuclein Meetings are a series that has been taking place every 2 years for about 12 years. The Synuclein Meetings bring together leading experts in the field of synuclein and related human conditions with the goal of discussing and advancing the research. In 2019, the Synuclein Meeting is taking place in Ofir, a city in the outskirts of Porto, Portugal. The meeting is entitled 'Synuclein Meeting 2019: Where we are and where we need to go'. It has now been 22 years since the initial report of the genetic and pathological association between alpha-synuclein and Parkinson's disease (PD). The field has grown and matured, and major advances have been made. We are witnessing exciting times, with the first clinical trials being conducted that target synuclein, and bring the hope of novel therapies for patients with PD and their families. However, we still face many challenges and need to address fundamental questions for the field to progress to where we need to go: having biomarkers and effective therapies for PD and other synucleinopathies. In this context, we have designed the Synuclein Meeting 2019 with a different format. The program will include sessions in the format of a round-table discussion, to break away from the more rigid format of regular scientific meetings based on oral presentations. Our goal was to create opportunities for discussing the major questions in the field of synuclein and related human disorders, and challenge dogmatic ideas that require a critical revision in light of the most recent knowledge. In this issue, we assembled a series of comprehensive overviews of major topics, questions, and challenges in the field, that will be discussed in the meeting. We are confident that this special issue will be an instrumental reference for inspiring novel paths for future discoveries in the synuclein field and generate other discussions in the scientific community. This is the Preface for the Special Issue "Synuclein". Cover Image for this issue: doi: 10.1111/jnc.14520.
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Affiliation(s)
- Tiago Fleming Outeiro
- Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Göttingen, Germany.,Max Planck Institute for Experimental Medicine, Göttingen, Germany.,Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, UK
| | - Tiago A Mestre
- Parkinson's Disease and Movement Disorders Center, Division of Neurology, Department of Medicine, The Ottawa Hospital Research Institute, Brain and Mind Research Institute, University of Ottawa, Ottawa, Canada
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46
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Conjugal multiple system atrophy: Computing chance or investigating real patients? Parkinsonism Relat Disord 2020; 75:122-123. [PMID: 32199744 DOI: 10.1016/j.parkreldis.2020.03.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 03/09/2020] [Indexed: 11/22/2022]
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Disruption of cellular proteostasis by H1N1 influenza A virus causes α-synuclein aggregation. Proc Natl Acad Sci U S A 2020; 117:6741-6751. [PMID: 32152117 DOI: 10.1073/pnas.1906466117] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Neurodegenerative diseases feature specific misfolded or misassembled proteins associated with neurotoxicity. The precise mechanisms by which protein aggregates first arise in the majority of sporadic cases have remained unclear. Likely, a first critical mass of misfolded proteins starts a vicious cycle of a prion-like expansion. We hypothesize that viruses, having evolved to hijack the host cellular machinery for catalyzing their replication, lead to profound disturbances of cellular proteostasis, resulting in such a critical mass of protein aggregates. Here, we investigated the effect of influenza virus (H1N1) strains on proteostasis of proteins associated with neurodegenerative diseases in Lund human mesencephalic dopaminergic cells in vitro and infection of Rag knockout mice in vivo. We demonstrate that acute H1N1 infection leads to the formation of α-synuclein and Disrupted-in-Schizophrenia 1 (DISC1) aggregates, but not of tau or TDP-43 aggregates, indicating a selective effect on proteostasis. Oseltamivir phosphate, an antiinfluenza drug, prevented H1N1-induced α-synuclein aggregation. As a cell pathobiological mechanism, we identified H1N1-induced blocking of autophagosome formation and inhibition of autophagic flux. In addition, α-synuclein aggregates appeared in infected cell populations connected to the olfactory bulbs following intranasal instillation of H1N1 in Rag knockout mice. We propose that H1N1 virus replication in neuronal cells can induce seeds of aggregated α-synuclein or DISC1 that may be able to initiate further detrimental downstream events and should thus be considered a risk factor in the pathogenesis of synucleinopathies or a subset of mental disorders. More generally, aberrant proteostasis induced by viruses may be an underappreciated factor in initiating protein misfolding.
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Lam I, Hallacli E, Khurana V. Proteome-Scale Mapping of Perturbed Proteostasis in Living Cells. Cold Spring Harb Perspect Biol 2020; 12:cshperspect.a034124. [PMID: 30910772 DOI: 10.1101/cshperspect.a034124] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Proteinopathies are degenerative diseases in which specific proteins adopt deleterious conformations, leading to the dysfunction and demise of distinct cell types. They comprise some of the most significant diseases of aging-from Alzheimer's disease to Parkinson's disease to type 2 diabetes-for which not a single disease-modifying or preventative strategy exists. Here, we survey approaches in tractable cellular and organismal models that bring us toward a more complete understanding of the molecular consequences of protein misfolding. These include proteome-scale profiling of genetic modifiers, as well as transcriptional and proteome changes. We describe assays that can capture protein interactomes in situ and distinct protein conformational states. A picture of cellular drivers and responders to proteotoxicity emerges from this work, distinguishing general alterations of proteostasis from cellular events that are deeply tied to the intrinsic function of the misfolding protein. These distinctions have consequences for the understanding and treatment of proteinopathies.
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Affiliation(s)
- Isabel Lam
- Ann Romney Center for Neurologic Disease, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115
| | - Erinc Hallacli
- Ann Romney Center for Neurologic Disease, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115
| | - Vikram Khurana
- Ann Romney Center for Neurologic Disease, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.,Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142.,Harvard Stem Cell Institute, Cambridge, Massachusetts 02138.,New York Stem Cell Foundation - Robertson Investigator
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Jellinger KA. Multiple system atrophy - a clinicopathological update. FREE NEUROPATHOLOGY 2020; 1:17. [PMID: 37283673 PMCID: PMC10209915 DOI: 10.17879/freeneuropathology-2020-2813] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 06/24/2020] [Indexed: 06/08/2023]
Abstract
Multiple system atrophy (MSA) is a fatal, adult-onset neurodegenerative disorder of uncertain etiology, clinically characterized by various combinations of Levo-dopa-unresponsive parkinsonism, and cerebellar, motor, and autonomic dysfunctions. MSA is an α-synucleinopathy with specific glioneuronal degeneration involving striatonigral, olivopontocerebellar, autonomic and peripheral nervous systems. The pathologic hallmark of this unique proteinopathy is the deposition of aberrant α-synuclein (αSyn) in both glia (mainly oligodendroglia) and neurons forming pathological inclusions that cause cell dysfunction and demise. The major variants are striatonigral degeneration (MSA with predominant parkinsonism / MSA-P) and olivopontocerebellar atrophy (MSA with prominent cerebellar ataxia / MSA-C). However, the clinical and pathological features of MSA are broader than previously considered. Studies in various mouse models and human patients have helped to better understand the molecular mechanisms that underlie the progression of the disease. The pathogenesis of MSA is characterized by propagation of disease-specific strains of αSyn from neurons to oligodendroglia and cell-to-cell spreading in a "prion-like" manner, oxidative stress, proteasomal and mitochondrial dysfunctions, myelin dysregulation, neuroinflammation, decreased neurotrophic factors, and energy failure. The combination of these mechanisms results in neurodegeneration with widespread demyelination and a multisystem involvement that is specific for MSA. Clinical diagnostic accuracy and differential diagnosis of MSA have improved by using combined biomarkers. Cognitive impairment, which has been a non-supporting feature of MSA, is not uncommon, while severe dementia is rare. Despite several pharmacological approaches in MSA models, no effective disease-modifying therapeutic strategies are currently available, although many clinical trials targeting disease modification, including immunotherapy and combined approaches, are under way. Multidisciplinary research to elucidate the genetic and molecular background of the noxious processes as the basis for development of an effective treatment of the hitherto incurable disorder are urgently needed.
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Nan H, Natori T, Ichinose Y, Koh K, Kobayashi F, Shindo K, Hashiyada M, Adachi N, Yamagata Z, Takiyama Y. Conjugal cerebellar type of multiple system atrophy: Person-to-person transmission? Parkinsonism Relat Disord 2019; 69:68-70. [DOI: 10.1016/j.parkreldis.2019.10.026] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 10/23/2019] [Accepted: 10/26/2019] [Indexed: 10/25/2022]
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