1. β-synuclein regulates the phase transitions and amyloid conversion of α-synuclein
- Author
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Xi Li, Linwei Yu, Xikai Liu, Tianyi Shi, Yu Zhang, Yushuo Xiao, Chen Wang, Liangliang Song, Ning Li, Xinran Liu, Yuchen Chen, Robert B. Petersen, Xiang Cheng, Weikang Xue, Yanxun V. Yu, Li Xu, Ling Zheng, Hong Chen, and Kun Huang
- Subjects
Science - Abstract
Abstract Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB) are neurodegenerative disorders characterized by the accumulation of α-synuclein aggregates. α-synuclein forms droplets via liquid-liquid phase separation (LLPS), followed by liquid-solid phase separation (LSPS) to form amyloids, how this process is physiologically-regulated remains unclear. β-synuclein colocalizes with α-synuclein in presynaptic terminals. Here, we report that β-synuclein partitions into α-synuclein condensates promotes the LLPS, and slows down LSPS of α-synuclein, while disease-associated β-synuclein mutations lose these capacities. Exogenous β-synuclein improves the movement defects and prolongs the lifespan of an α-synuclein-expressing NL5901 Caenorhabditis elegans strain, while disease-associated β-synuclein mutants aggravate the symptoms. Decapeptides targeted at the α-/β-synuclein interaction sites are rationally designed, which suppress the LSPS of α-synuclein, rescue the movement defects, and prolong the lifespan of C. elegans NL5901. Together, we unveil a Yin-Yang balance between α- and β-synuclein underlying the normal and disease states of PD and DLB with therapeutical potentials.
- Published
- 2024
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