Journal ArticleDOI
|[alpha]|-Synuclein is phosphorylated in synucleinopathy lesions
Hideo Fujiwara,Masato Hasegawa,Naoshi Dohmae,Akiko Kawashima,Eliezer Masliah,Matthew S. Goldberg,Jie Shen,Koji Takio,Takeshi Iwatsubo +8 more
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TLDR
It is shown by mass spectrometry analysis and studies with an antibody that specifically recognizes phospho-Ser 129 of α-synuclein, that this residue is selectively and extensively phosphorylated in synucleinopathy lesions and promoted fibril formation in vitro.Abstract:
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.read more
Citations
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Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1
Eriza Maria Valente,Patrick M. Abou-Sleiman,Viviana Caputo,Miratul M. K. Muqit,Kirsten Harvey,Suzana Gispert,Zeeshan Ali,Domenico Del Turco,Anna Rita Bentivoglio,Daniel G. Healy,Alberto Albanese,Robert L. Nussbaum,Rafael González-Maldonado,Thomas Deller,S Salvi,Pietro Cortelli,William P. Gilks,David S. Latchman,Roberk J. Harvey,Bruno Dallapiccola,Georg Auburger,Nicholas W. Wood +21 more
TL;DR: The identification of two homozygous mutations affecting the PINK1 kinase domain in three consanguineous PARK6 families provide a direct molecular link between mitochondria and the pathogenesis of PD.
Journal ArticleDOI
TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis
Tetsuaki Arai,Masato Hasegawa,Haruhiko Akiyama,Kenji Ikeda,Takashi Nonaka,Hiroshi Mori,David M. A. Mann,Kuniaki Tsuchiya,Mari Yoshida,Yoshio Hashizume,Tatsuro Oda +10 more
TL;DR: The common occurrence of intracellular accumulations of TDP-43 supports the hypothesis that these disorders represent a clinicopathological entity of a single disease, and suggests that they can be newly classified as a proteinopathy of T DP-43.
Journal ArticleDOI
Pathological α-Synuclein Transmission Initiates Parkinson-like Neurodegeneration in Nontransgenic Mice
Kelvin C. Luk,Victoria M. Kehm,Jenna C. Carroll,Bin Zhang,Patrick O’Brien,John Q. Trojanowski,Virginia M.-Y. Lee +6 more
TL;DR: It is found that in wild-type nontransgenic mice, a single intrastriatal inoculation of synthetic α- Syn fibrils led to the cell-to-cell transmission of pathologic α-Syn and Parkinson’s-like Lewy pathology in anatomically interconnected regions.
Journal ArticleDOI
Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death.
Laura A. Volpicelli-Daley,Kelvin C. Luk,Tapan P. Patel,Selcuk A. Tanik,Dawn M. Riddle,Anna Stieber,David F. Meaney,John Q. Trojanowski,Virginia M.-Y. Lee +8 more
TL;DR: It is demonstrated that preformed fibrils generated from full-length and truncated recombinant α-syn enter primary neurons, probably by adsorptive-mediated endocytosis, and promote recruitment of soluble endogenousα-syn into insoluble PD-like LBs and LNs.
Journal ArticleDOI
Phosphorylation of Ser-129 Is the Dominant Pathological Modification of α-Synuclein in Familial and Sporadic Lewy Body Disease
John P. Anderson,Donald Walker,Jason Goldstein,Rian de Laat,Kelly Banducci,Russell J. Caccavello,Robin Barbour,Jiping Huang,Kristin Kling,Michael K. Lee,Linnea Diep,Pamela S. Keim,Xiaofeng Shen,Tim Chataway,Michael G. Schlossmacher,Peter A. Seubert,Dale B. Schenk,Sukanto Sinha,Wei Ping Gai,Tamie J. Chilcote +19 more
TL;DR: A comprehensive, unbiased inventory of synuclein forms present in Lewy bodies from patients with dementia with Lewy body was carried out using two-dimensional immunoblot analysis, novel enzyme-linked immunosorbent assays with modification-specific Synuclein antibodies, and mass spectroscopy as mentioned in this paper.
References
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Journal ArticleDOI
Mutation in the α-synuclein gene identified in families with Parkinson's disease
Mihael H. Polymeropoulos,Christian Lavedan,Elisabeth Leroy,Susan E. Ide,Anindya Dehejia,Amalia Dutra,Brian L. Pike,Holly Root,Jeffrey Rubenstein,Rebecca Boyer,Edward S. Stenroos,Settara C. Chandrasekharappa,Aglaia Athanassiadou,Theodore Papapetropoulos,William G. Johnson,Alice Lazzarini,Roger C. Duvoisin,Giuseppe Di Iorio,Lawrence I. Golbe,Robert L. Nussbaum +19 more
TL;DR: A mutation was identified in the α-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype.
Journal ArticleDOI
Alpha-synuclein in Lewy bodies.
Maria Grazia Spillantini,Marie L. Schmidt,Virginia M.-Y. Lee,John Q. Trojanowski,Ross Jakes,Michel Goedert +5 more
TL;DR: Strong staining of Lewy bodies from idiopathic Parkinson's disease with antibodies for α-synuclein, a presynaptic protein of unknown function which is mutated in some familial cases of the disease, indicates that the LewY bodies from these two diseases may have identical compositions.
Journal ArticleDOI
Proteomics to study genes and genomes
TL;DR: Proteomics can be divided into three main areas: protein micro-characterization for large-scale identification of proteins and their post-translational modifications; ‘differential display’ proteomics for comparison of protein levels with potential application in a wide range of diseases; and studies of protein–protein interactions using techniques such as mass spectrometry or the yeast two-hybrid system.
Journal ArticleDOI
Dopaminergic Loss and Inclusion Body Formation in α-Synuclein Mice: Implications for Neurodegenerative Disorders
Eliezer Masliah,Edward Rockenstein,Isaac Veinbergs,Margaret Mallory,Makoto Hashimoto,Ayako Takeda,Yutaka Sagara,Abbyann Sisk,Lennart Mucke +8 more
TL;DR: Results suggest that accumulation of wild-type alpha-synuclein may play a causal role in Parkinson's disease and related conditions.
Journal ArticleDOI
Acceleration of oligomerization, not fibrillization, is a shared property of both α-synuclein mutations linked to early-onset Parkinson's disease: Implications for pathogenesis and therapy
Kelly A. Conway,Seung Jae Lee,Jean-Christophe Rochet,Tomas T. Ding,Robin E. Williamson,Peter T. Lansbury +5 more
TL;DR: In this in vitro study, drug candidates that inhibit alpha-synuclein fibrillization but do not block its oligomerization could mimic the A30P mutation and thus may accelerate disease progression.
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