化学
单体
蛋白质聚集
生物物理学
锰
淀粉样蛋白(真菌学)
过渡(遗传学)
相(物质)
结晶学
生物化学
生物
基因
有机化学
无机化学
聚合物
作者
Bin Xu,Shuai Huang,Yinghui Liu,Chun Wan,Yuanyuan Gu,Dianliang Wang,Haijia Yu
标识
DOI:10.1016/j.jbc.2021.101469
摘要
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.
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