Post-translational modifications of soluble α-synuclein regulate the amplification of pathological α-synuclein

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 PeterssonJohn Q. Trojanowski, Virginia M.Y. Lee, Chao Peng

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

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 Parkinsonʼs 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 Parkinsonʼs 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.

Original languageEnglish
Pages (from-to)213-225
Number of pages13
JournalNature neuroscience
Volume26
Issue number2
DOIs
StatePublished - Feb 2023

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