Manganese promotes α-synuclein amyloid aggregation through the induction of protein phase transition
| Autor: | Bingkuan Xu, Shuai Huang, Yinghui Liu, Chun Wan, Yuanyuan Gu, Dianliang Wang, Haijia Yu |
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| Rok vydání: | 2022 |
| Předmět: |
Amyloid
animal diseases α-Syn α-synuclein Amyloidogenic Proteins Protein Aggregation Pathological Biochemistry condensate Protein Aggregates α-synuclein ThT thioflavin T Humans heterocyclic compounds Molecular Biology PD Parkinson’s disease Manganese ThS thioflavin S aggregation FRAP fluorescence recovery after photobleaching Parkinson Disease Amyloidosis Cell Biology nervous system diseases LLPS liquid–liquid phase separation IDR intrinsically disordered region nervous system phase transition health occupations alpha-Synuclein liquid–liquid phase separation (LLPS) Lewy Bodies Research Article |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| DOI: | 10.1016/j.jbc.2021.101469 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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