Manganese promotes α-synuclein amyloid aggregation through the induction of protein phase transition

• Published in: The Journal of biological chemistry Vol. 298; no. 1; p. 101469
• Main Authors: Xu, Bingkuan, Huang, Shuai, Liu, Yinghui, Wan, Chun, Gu, Yuanyuan, Wang, Dianliang, Yu, Haijia
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2022; American Society for Biochemistry and Molecular Biology
• Subjects: aggregation; alpha-Synuclein - metabolism; Amyloid - metabolism; Amyloidogenic Proteins - metabolism; Amyloidosis - metabolism; condensate; Humans; Lewy Bodies - metabolism; liquid–liquid phase separation (LLPS); manganese; Manganese - metabolism; Parkinson Disease - metabolism; phase transition; Protein Aggregates; Protein Aggregation, Pathological - metabolism; α-synuclein; LLPS; ThT; aggregation; condensate; manganese; liquid–liquid phase separation (LLPS); PD; α-Syn; IDR; FRAP; phase transition; α-synuclein; ThS
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/j.jbc.2021.101469

α-Synuclein (α-Syn) is the major protein component of Lewy bodies, a key pathological feature of Parkinson’s disease (PD). The manganese ion Mn2+ has been identified as an environmental risk factor of PD. However, it remains unclear how Mn2+ regulates α-Syn aggregation. Here, we discovered that Mn2+accelerates α-Syn amyloid aggregation through the regulation of protein phase separation. We found that Mn2+ not only promotes α-Syn liquid-to-solid phase transition but also directly induces soluble α-Syn monomers to form solid-like condensates. Interestingly, the lipid membrane is integrated into condensates during Mn2+-induced α-Syn phase transition; however, the preformed Mn2+/α-syn condensates can only recruit lipids to the surface of condensates. In addition, this phase transition can largely facilitate α-Syn amyloid aggregation. Although the Mn2+-induced condensates do not fuse, our results demonstrated that they could recruit soluble α-Syn monomers into the existing condensates. Furthermore, we observed that a manganese chelator reverses Mn2+-induced α-Syn aggregation during the phase transition stage. However, after maturation, α-Syn aggregation becomes irreversible. These findings demonstrate that Mn2+ facilitates α-Syn phase transition to accelerate the formation of α-Syn aggregates and provide new insights for targeting α-Syn phase separation in PD treatment.