title: Phosphorylation induces distinct alpha-synuclein strain formation.
abstract: Synucleinopathies are a group of neurodegenerative diseases associated with alpha-synuclein (α-Syn) aggregation. Recently, increasing evidence has demonstrated the existence of different structural characteristics or 'strains' of α-Syn, supporting the concept that synucleinopathies share several common features with prion diseases and possibly explaining how a single protein results in different clinical phenotypes within synucleinopathies. In earlier studies, the different strains were generated through the regulation of solution conditions, temperature, or repetitive seeded fibrillization in vitro. Here, we synthesize homogeneous α-Syn phosphorylated at serine 129 (pS129 α-Syn), which is highly associated with the pathological changes, and demonstrate that phosphorylation at Ser129 induces α-Syn to form a distinct strain with different structures, propagation properties, and higher cytotoxicity compared with the wild-type α-Syn. The results are the first demonstration that post-translational modification of α-Syn can induce different strain formation, offering a new mechanism for strain formation.
authors.affiliation: Department of Chemistry, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, P. R. China.
authors.forename: Meng-Rong
authors.initials: MR
authors.lastname: Ma
authors.affiliation: Department of Chemistry, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, P. R. China.
authors.forename: Zhi-Wen
authors.initials: ZW
authors.lastname: Hu
authors.affiliation: Department of Chemistry, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, P. R. China.
authors.forename: Yu-Fen
authors.initials: YF
authors.lastname: Zhao
authors.affiliation: Department of Chemistry, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, P. R. China.
authors.forename: Yong-Xiang
authors.initials: YX
authors.lastname: Chen
authors.affiliation: Department of Chemistry, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, P. R. China.|Beijing Institute for Brain Disorders, Beijing 100069, P. R. China.
authors.forename: Yan-Mei
authors.initials: YM
authors.lastname: Li
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D010766:Phosphorylation; D066263:Protein Aggregation, Pathological / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: C497604:SNCA protein, human; D051844:alpha-Synuclein