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

被引:2
作者
Li, Xi [1 ,2 ]
Yu, Linwei [1 ,2 ]
Liu, Xikai [3 ]
Shi, Tianyi [1 ,2 ]
Zhang, Yu [1 ,2 ]
Xiao, Yushuo [1 ,2 ]
Wang, Chen [1 ,2 ]
Song, Liangliang [1 ,2 ]
Li, Ning [1 ,2 ]
Liu, Xinran [1 ,2 ]
Chen, Yuchen [1 ,2 ]
Petersen, Robert B. [4 ]
Cheng, Xiang [5 ]
Xue, Weikang [6 ]
Yu, Yanxun V. [6 ]
Xu, Li [1 ,2 ]
Zheng, Ling [3 ]
Chen, Hong [1 ,2 ]
Huang, Kun [1 ,2 ,7 ]
机构
[1] Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Pharm, Wuhan, Peoples R China
[2] Huazhong Univ Sci & Technol, State Key Lab Diag & Treatment Severe Zoonot Infec, Wuhan, Peoples R China
[3] Wuhan Univ, Coll Life Sci, Frontier Sci Ctr Immunol & Metab, Hubei Key Lab Cell Homeostasis, Wuhan, Peoples R China
[4] Cent Michigan Univ, Fdn Sci, Coll Med, Mt Pleasant, MI USA
[5] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Cardiol, Wuhan, Peoples R China
[6] Wuhan Univ, Zhongnan Hosp, Med Res Inst, Dept Neurol, Wuhan, Peoples R China
[7] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Rong Cheng Biomed Ctr, Wuhan, Peoples R China
基金
国家重点研发计划; 中国国家自然科学基金;
关键词
PARKINSONS-DISEASE; LEWY BODIES; DEMENTIA; AGGREGATION; FIBRILLATION; PROPAGATION; SEPARATION; ELEGANS; CELLS; TRIAL;
D O I
10.1038/s41467-024-53086-8
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB) are neurodegenerative disorders characterized by the accumulation of alpha-synuclein aggregates. alpha-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. beta-synuclein colocalizes with alpha-synuclein in presynaptic terminals. Here, we report that beta-synuclein partitions into alpha-synuclein condensates promotes the LLPS, and slows down LSPS of alpha-synuclein, while disease-associated beta-synuclein mutations lose these capacities. Exogenous beta-synuclein improves the movement defects and prolongs the lifespan of an alpha-synuclein-expressing NL5901 Caenorhabditis elegans strain, while disease-associated beta-synuclein mutants aggravate the symptoms. Decapeptides targeted at the alpha-/beta-synuclein interaction sites are rationally designed, which suppress the LSPS of alpha-synuclein, rescue the movement defects, and prolong the lifespan of C. elegans NL5901. Together, we unveil a Yin-Yang balance between alpha- and beta-synuclein underlying the normal and disease states of PD and DLB with therapeutical potentials. The authors report a Yin-Yang balance between alpha-Synuclein and beta-Synuclein via regulating phase separation in physiological states and Parkinson's disease. AI-designed peptides mitigate the symptoms and prolong the lifespan of C. elegans PD models.
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页数:17
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