Post-translational modifications of soluble α-synuclein regulate the amplification of pathological α-synuclein
Autor: | Shujing Zhang, Ruowei Zhu, Buyan Pan, Hong Xu, Modupe F. Olufemi, Ronald J. Gathagan, Yuanxi Li, Luyan Zhang, Jasmine Zhang, Wenxuan Xiang, Eliot Masahiro Kagan, Xingjun Cao, Chaoxing Yuan, Soo-Jung Kim, Christopher K. Williams, Shino Magaki, Harry V. Vinters, Hilal A. Lashuel, Benjamin A. Garcia, E. James Petersson, John Q. Trojanowski, Virginia M.-Y. Lee, Chao Peng |
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Rok vydání: | 2023 |
Předmět: |
Chromatography
Liquid Parkinson's Disease Neurology & Neurosurgery Synucleinopathies General Neuroscience Post-Translational Neurosciences Parkinson Disease Neurodegenerative Diseases Neurodegenerative Brain Disorders Tandem Mass Spectrometry Neurological alpha-Synuclein Acquired Cognitive Impairment Humans 2.1 Biological and endogenous factors Psychology Cognitive Sciences Aetiology Protein Processing |
Zdroj: | Nature neuroscience, vol 26, iss 2 |
ISSN: | 1546-1726 1097-6256 |
Popis: | Cell-to-cell transmission and subsequent amplification of pathological proteins promote neurodegenerative disease progression. Most research on this has focused on pathological protein seeds, but how their normal counterparts, which are converted to pathological forms during transmission, regulate transmission is less understood. Here we show in cultured cells that phosphorylation of soluble, nonpathological α-synuclein (α-Syn) at previously identified sites dramatically affects the amplification of pathological α-Syn, which underlies Parkinson's disease and other α-synucleinopathies, in a conformation- and phosphorylation site-specific manner. We performed LC-MS/MS analyses on soluble α-Syn purified from Parkinson's disease and other α-synucleinopathies, identifying many new α-Syn post-translational modifications (PTMs). In addition to phosphorylation, acetylation of soluble α-Syn also modified pathological α-Syn transmission in a site- and conformation-specific manner. Moreover, phosphorylation of soluble α-Syn could modulate the seeding properties of pathological α-Syn. Our study represents the first systematic analysis how of soluble α-Syn PTMs affect the spreading and amplification of pathological α-Syn, which may affect disease progression. |
Databáze: | OpenAIRE |
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