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      The Synucleinopathies: Twenty Years On

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          Abstract

          In 2017, it is two hundred years since James Parkinson provided the first complete clinical description of the disease named after him, fifty years since the introduction of high-dose D,L-DOPA treatment and twenty years since α-synuclein aggregation came to the fore. In 1998, multiple system atrophy joined Parkinson’s disease and dementia with Lewy bodies as the third major synucleinopathy. Here we review our work, which led to the identification of α-synuclein in Lewy bodies, Lewy neurites and Papp-Lantos bodies, as well as what has happened since. Some of the experiments described were carried out in collaboration with ML Schmidt, JQ Trojanowski and VMY Lee.

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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 605 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.
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              Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease.

              K. A. Conway, J Harper, P. Lansbury (1998)
              Two mutations in the gene encoding alpha-synuclein have been linked to early-onset Parkinson's disease (PD). alpha-Synuclein is a component of Lewy bodies, the fibrous cytoplasmic inclusions characteristic of nigral dopaminergic neurons in the PD brain. This connection between genetics and pathology suggests that the alpha-synuclein mutations may promote PD pathogenesis by accelerating Lewy body formation. To test this, we studied alpha-synuclein folding and aggregation in vitro, in the absence of other Lewy body-associated molecules. We demonstrate here that both mutant forms of alpha-synuclein (A53T and A30P) are, like wild-type alpha-synuclein (WT), disordered in dilute solution. However, at higher concentrations, Lewy body-like fibrils and discrete spherical assemblies are formed; most rapidly by A53T. Thus, mutation-induced acceleration of alpha-synuclein fibril formation may contribute to the early onset of familial PD.
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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): 6 March 2017
                Publication date (Electronic, collection): 2017
                Volume: 7
                Issue: Suppl 1 , Milestones in 200 years of Parkinson’s Disease Research
                Pages: S53-S71
                Affiliations
                [a ]MRC Laboratory of Molecular Biology , Cambridge, UK
                [b ]Department of Clinical Neurosciences, Clifford Allbutt Building, Cambridge, AH, UK
                Author notes
                [* ]Correspondence to: Michel Goedert, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK. Tel.: +44 12234 267056; Fax: +44 1223 268305; E-mail: mg@ 123456mrc-lmb.cam.ac.uk .
                Article
                Publisher ID: JPD179005
                DOI: 10.3233/JPD-179005
                PMC ID: 5345650
                PubMed ID: 28282814
                SO-VID: 054d7938-6d12-4896-b993-69d1e857a02c
                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
                Date accepted : 27 January 2017
                Categories
                Subject: Review

                Keywords: alpha-synuclein,parkinson’s disease,dementia with lewy bodies,multiple system atrophy,protein aggregation,aggregate propagation,neurodegeneration
                Data availability:
                Keywords: alpha-synuclein, parkinson’s disease, dementia with lewy bodies, multiple system atrophy, protein aggregation, aggregate propagation, neurodegeneration

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