2. Academic Validation
  3. β-synuclein regulates the phase transitions and amyloid conversion of α-synuclein

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

  • Nat Commun. 2024 Oct 9;15(1):8748. doi: 10.1038/s41467-024-53086-8.
Xi Li 1,  Linwei Yu 1,  Xikai Liu 2,  Tianyi Shi 1,  Yu Zhang 1,  Yushuo Xiao 1,  Chen Wang 1,  Liangliang Song 1,  Ning Li 1,  Xinran Liu 1,  Yuchen Chen 1,  Robert B Petersen 3,  Xiang Cheng 4,  Weikang Xue 5,  Yanxun V Yu 5,  Li Xu 1,  Ling Zheng 2,  Hong Chen 6,  Kun Huang 7 8
Affiliations

Affiliations

  • 1 School of Pharmacy, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Hubei Key Laboratory of Cell Homeostasis, Frontier Science Center for Immunology and Metabolism, College of Life Sciences, Wuhan University, Wuhan, China.
  • 3 Foundational Sciences, Central Michigan University College of Medicine, Mt. Pleasant, MI, USA.
  • 4 Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 5 Department of Neurology, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
  • 6 School of Pharmacy, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China. hongchen2017@hust.edu.cn.
  • 7 School of Pharmacy, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China. kunhuang@hust.edu.cn.
  • 8 Tongji-Rong Cheng Biomedical Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. kunhuang@hust.edu.cn.
PMID: 39384788 DOI: 10.1038/s41467-024-53086-8
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.

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