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Manganese promotes α-synuclein amyloid aggregation through the induction of protein phase transition
Bingkuan Xu1, Shuai Huang1, Yinghui Liu1
1Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.
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 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.
Insights
Manganese (Mn2+) accelerates Parkinson's disease pathology by promoting alpha-synuclein (α-Syn) protein aggregation through phase separation. This process is reversible in early stages but becomes irreversible once α-Syn aggregates mature.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- Alpha-synuclein (α-Syn) aggregation into Lewy bodies is central to Parkinson's disease (PD) pathogenesis.
- Manganese (Mn2+) exposure is an environmental risk factor linked to PD, but its mechanism of action on α-Syn remains unclear.
Purpose of the Study:
- To investigate the role of Mn2+ in regulating α-Syn aggregation via protein phase separation.
- To elucidate the impact of Mn2+ on the transition of α-Syn from soluble monomers to aggregated forms.
Main Methods:
- Studied the effect of Mn2+ on α-Syn liquid-to-solid phase transition and condensate formation.
- Investigated the interaction of lipid membranes with Mn2+-induced α-Syn condensates.
- Assessed the reversibility of Mn2+-induced α-Syn aggregation using a manganese chelator.
Main Results:
- Mn2+ promotes α-Syn liquid-to-solid phase transition, inducing the formation of solid-like α-Syn condensates.
- Lipid membranes integrate into condensates during Mn2+-induced phase transition, and preformed condensates recruit lipids to their surface.
- Mn2+-induced α-Syn aggregation is reversible during the phase transition stage but becomes irreversible upon condensate maturation.
- Mn2+-induced condensates recruit soluble α-Syn monomers, further facilitating aggregation.
Conclusions:
- Mn2+ accelerates α-Syn aggregation by inducing phase separation, offering a novel therapeutic target for Parkinson's disease.
- Understanding Mn2+-mediated α-Syn phase separation provides critical insights into PD pathogenesis and potential treatment strategies.
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