文献类型：期刊文献

英文题名：Post-translational modifications of soluble α-synuclein regulate the amplification of pathological α-synuclein

作者：Zhang, Shujing[1];Zhu, Ruowei[1];Pan, Buyan[2];Xu, Hong[3,4];Olufemi, Modupe F.[3,4];Gathagan, Ronald J.[3,4];Li, Yuanxi[1,5,6];Zhang, Luyan[1];Zhang, Jasmine[1];Xiang, Wenxuan[1];Kagan, Eliot Masahiro[1];Cao, Xingjun[7];Yuan, Chaoxing[8];Kim, Soo-Jung[3,4];Williams, Christopher K.[9];Magaki, Shino[9];Vinters, Harry V.[10];Lashuel, Hilal A.[11];Garcia, Benjamin A.[12];Petersson, E. James[2];Trojanowski, John Q.[3,4];Lee, Virginia M. -Y.[3,4];Peng, Chao[1,13,14]

机构：[1]Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA;[2]Univ Penn, Sch Arts & Sci, Dept Chem, Philadelphia, PA USA;[3]Univ Penn, Inst Aging, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA;[4]Univ Penn, Ctr Neurodegenerat Dis Res, Perelman Sch Med, Philadelphia, PA 19104 USA;[5]East China Univ Sci & Technol, Inst Cognit Neurodynam, Shanghai, Peoples R China;[6]East China Univ Sci & Technol, Sch Math, Shanghai, Peoples R China;[7]Innovent Biol Inc, Suzhou, Peoples R China;[8]Alexion Pharmaceut Inc, New Haven, CT USA;[9]Univ Calif Los Angeles, Ronald Reagan UCLA Med Ctr, Sect Neuropathol, Dept Pathol & Lab Med, Los Angeles, CA USA;[10]Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA USA;[11]Washington Univ St Louis, Dept Biochem & Mol Biophys, St. Louis, MO USA;[12]Univ Calif Los Angeles, Mol Biol Inst, Los Angeles, CA 90095 USA;[13]Univ Calif Los Angeles, Res Inst 3Brain, Los Angeles, CA 90095 USA;[14]Univ Calif Los Angeles, Mary S Easton Ctr Alzheimers Res, Los Angeles, CA 90095 USA

年份：2023

卷号：26

期号：2

起止页码：213

外文期刊名：NATURE NEUROSCIENCE

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000919750900002)】；

基金：We thank Quantitative Proteomics Resource Core of School of Medicine at the University of Pennsylvania and Proteomics Core at Children's Hospital of Philadelphia (CHOP) for performing the LC-MS/MS analysis. We thank S. Seeholzer, L. Spruce, H. Ding, H. Fazelinia and H. Lee (from CHOP) for helping with LC-MS/MS experiments. We thank D. Riddle for providing primary neurons, L. Romero for helping with quantification and all the other members of the Center for Neurodegenerative Disease Research for their support. We thank Lucy Ruoxi Shi for helping with the cartoon illustration of this work. This work was supported by NIH/NINDS Udall Center under grant NS53488 (to V.M.-Y.L.), NIA under grant U19 AG062418 (Center on Alpha-Synuclein Strains in Alzheimer's Disease and Related Dementias) (to V.M.-Y.L.), NIH/NINDS R01-NS103873 to E.J.P. (to V.M.-Y.L.), NIH/NINDS R01-NS128964 (to C.P.), CurePSP grant 672-2020-12 (to C.P.), the Ofer Nimerovsky Family Fund (to V.M.-Y.L.), the Jeff and Anne Keefer Fund (to V.M.-Y.L.) and the MSA Coalition Seed Grant (to C.P. and V.M.-Y.L.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

语种：英文

摘要：Pathological alpha-synuclein (alpha-Syn) spreading is critical for the progression of many neurodegenerative diseases. The authors demonstrate that soluble alpha-Syn post-translational modifications (PTMs) dramatically modulate pathological alpha-synuclein spreading. 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 alpha-synuclein (alpha-Syn) at previously identified sites dramatically affects the amplification of pathological alpha-Syn, which underlies Parkinson & apos;s disease and other alpha-synucleinopathies, in a conformation- and phosphorylation site-specific manner. We performed LC-MS/MS analyses on soluble alpha-Syn purified from Parkinson & apos;s disease and other alpha-synucleinopathies, identifying many new alpha-Syn post-translational modifications (PTMs). In addition to phosphorylation, acetylation of soluble alpha-Syn also modified pathological alpha-Syn transmission in a site- and conformation-specific manner. Moreover, phosphorylation of soluble alpha-Syn could modulate the seeding properties of pathological alpha-Syn. Our study represents the first systematic analysis how of soluble alpha-Syn PTMs affect the spreading and amplification of pathological alpha-Syn, which may affect disease progression.