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
  • 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. [email protected].
  • 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. [email protected].
  • 8. Tongji-Rong Cheng Biomedical Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
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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