Manganese promotes α-synuclein amyloid aggregation through the induction of protein phase transition
Bingkuan Xu, Shuai Huang, Yinghui Liu, Chun Wan, Yuanyuan Gu, Dianliang Wang, Haijia Yu
Abstract
α-Synuclein (α-Syn) is the major protein component of Lewy bodies, a key pathological feature of Parkinson's disease (PD). The manganese ion Mn 2+ has been identified as an environmental risk factor of PD. However, it remains unclear how Mn 2+ regulates α-Syn aggregation. Here, we discovered that Mn 2+ accelerates α-Syn amyloid aggregation through the regulation of protein phase separation. We found that Mn 2+ 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 Mn 2+ -induced α-Syn phase transition; however, the preformed Mn 2+ /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 Mn 2+ -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 Mn 2+ -induced α-Syn aggregation during the phase transition stage. However, after maturation, α-Syn aggregation becomes irreversible. These findings demonstrate that Mn 2+ 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.