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      The Synaptic Function of α-Synuclein

      review-article
      Author(s): *
      Publication date (Electronic, pub):
      Publication date (Electronic, collection):
      Journal: Journal of Parkinson's Disease
      Publisher: IOS Press
      Keywords: α-synuclein, synapse, membranes, SNARE, neurotransmitter release, synaptic vesicles

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          Abstract

          α-Synuclein is an abundant neuronal protein which localizes predominantly to presynaptic terminals, and is strongly linked genetically and pathologically to Parkinson’s disease and other neurodegenerative diseases. While the accumulation of α-synuclein in the form of misfolded oligomers and large aggregates defines multiple neurodegenerative diseases called “synucleinopathies”, its cellular function has remained largely unclear, and is the subject of intense investigation. In this review, I focus on the structural characteristics of α-synuclein, its cellular and subcellular localization, and discuss how this relates to its function in neurons, in particular at the neuronal synapse.

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          Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis.

          Rakez Kayed, Elizabeth Head, Jennifer L Thompson … (2003)
          Soluble oligomers are common to most amyloids and may represent the primary toxic species of amyloids, like the Abeta peptide in Alzheimer's disease (AD). Here we show that all of the soluble oligomers tested display a common conformation-dependent structure that is unique to soluble oligomers regardless of sequence. The in vitro toxicity of soluble oligomers is inhibited by oligomer-specific antibody. Soluble oligomers have a unique distribution in human AD brain that is distinct from fibrillar amyloid. These results indicate that different types of soluble amyloid oligomers have a common structure and suggest they share a common mechanism of toxicity.
          Article 0 comments Cited 857 times – based on 0 reviews     Review now
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            alpha-Synuclein is phosphorylated in synucleinopathy lesions.

            Hideo Fujiwara, Masato Hasegawa, Naoshi Dohmae … (2002)
            The deposition of the abundant presynaptic brain protein alpha-synuclein as fibrillary aggregates in neurons or glial cells is a hallmark lesion in a subset of neurodegenerative disorders. These disorders include Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy, collectively referred to as synucleinopathies. Importantly, the identification of missense mutations in the alpha-synuclein gene in some pedigrees of familial PD has strongly implicated alpha-synuclein in the pathogenesis of PD and other synucleinopathies. However, specific post-translational modifications that underlie the aggregation of alpha-synuclein in affected brains have not, as yet, been identified. Here, we show by mass spectrometry analysis and studies with an antibody that specifically recognizes phospho-Ser 129 of alpha-synuclein, that this residue is selectively and extensively phosphorylated in synucleinopathy lesions. Furthermore, phosphorylation of alpha-synuclein at Ser 129 promoted fibril formation in vitro. These results highlight the importance of phosphorylation of filamentous proteins in the pathogenesis of neurodegenerative disorders.
            Article 0 comments Cited 601 times – based on 0 reviews     Review now
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              alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with lewy bodies.

              M Spillantini, R A Crowther, R. Jakes … (1998)
              Lewy bodies and Lewy neurites are the defining neuropathological characteristics of Parkinson's disease and dementia with Lewy bodies. They are made of abnormal filamentous assemblies of unknown composition. We show here that Lewy bodies and Lewy neurites from Parkinson's disease and dementia with Lewy bodies are stained strongly by antibodies directed against amino-terminal and carboxyl-terminal sequences of alpha-synuclein, showing the presence of full-length or close to full-length alpha-synuclein. The number of alpha-synuclein-stained structures exceeded that immunoreactive for ubiquitin, which is currently the most sensitive marker of Lewy bodies and Lewy neurites. Staining for alpha-synuclein thus will replace staining for ubiquitin as the preferred method for detecting Lewy bodies and Lewy neurites. We have isolated Lewy body filaments by a method used for the extraction of paired helical filaments from Alzheimer's disease brain. By immunoelectron microscopy, extracted filaments were labeled strongly by anti-alpha-synuclein antibodies. The morphologies of the 5- to 10-nm filaments and their staining characteristics suggest that extended alpha-synuclein molecules run parallel to the filament axis and that the filaments are polar structures. These findings indicate that alpha-synuclein forms the major filamentous component of Lewy bodies and Lewy neurites.
              Article 0 comments Cited 559 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Parkinsons Dis
                Journal ID (iso-abbrev): J Parkinsons Dis
                Journal ID (publisher-id): JPD
                Title: Journal of Parkinson's Disease
                Publisher: IOS Press (Nieuwe Hemweg 6B, 1013 BG Amsterdam, The Netherlands )
                ISSN (Print): 1877-7171
                ISSN (Electronic): 1877-718X
                Publication date (Electronic, pub): 8 October 2015
                Publication date (Electronic, collection): 2015
                Volume: 5
                Issue: 4
                Pages: 699-713
                Affiliations
                [1]Appel Institute for Alzheimer’s Disease Research, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College , New York, NY, USA
                Author notes
                [* ]Correspondence to: Jacqueline Burré, Appel Institute for Alzheimer’s Disease Research, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, 413 East 69th St, New York, NY 10021, USA. Tel.: +1 646 962 6155; Fax: +1 646 962 0572; E-mail: jab2058@ 123456med.cornell.edu
                Article
                Publisher ID: JPD150642
                DOI: 10.3233/JPD-150642
                PMC ID: 4927875
                PubMed ID: 26407041
                SO-VID: 708c0d08-e4f5-4784-9e9e-caeaea002460
                Copyright © IOS Press and the authors. All rights reserved
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Categories
                Subject: Review

                Keywords: α-synuclein,synapse,membranes,snare,neurotransmitter release,synaptic vesicles
                Data availability:
                Keywords: α-synuclein, synapse, membranes, snare, neurotransmitter release, synaptic vesicles

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