β-synuclein regulates the phase transitions and amyloid conversion of α-synuclein

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 ()
Additional contact information
Xi Li: Huazhong University of Science and Technology
Linwei Yu: Huazhong University of Science and Technology
Xikai Liu: Wuhan University
Tianyi Shi: Huazhong University of Science and Technology
Yu Zhang: Huazhong University of Science and Technology
Yushuo Xiao: Huazhong University of Science and Technology
Chen Wang: Huazhong University of Science and Technology
Liangliang Song: Huazhong University of Science and Technology
Ning Li: Huazhong University of Science and Technology
Xinran Liu: Huazhong University of Science and Technology
Yuchen Chen: Huazhong University of Science and Technology
Robert B. Petersen: Central Michigan University College of Medicine
Xiang Cheng: Huazhong University of Science and Technology
Weikang Xue: Zhongnan Hospital of Wuhan University, Wuhan University
Yanxun V. Yu: Zhongnan Hospital of Wuhan University, Wuhan University
Li Xu: Huazhong University of Science and Technology
Ling Zheng: Wuhan University
Hong Chen: Huazhong University of Science and Technology
Kun Huang: Huazhong University of Science and Technology

Nature Communications, 2024, vol. 15, issue 1, 1-17

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.

Date: 2024
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DOI: 10.1038/s41467-024-53086-8

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