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

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.