β-synuclein regulates the phase transitions and amyloid conversion of α-synuclein
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.
Authors
- Xiang Cheng (ORCID: https://orcid.org/0000-0002-6287-3128)
- Kun Huang (ORCID: https://orcid.org/0000-0002-0808-2325)
- Yushuo Xiao
- Tianyi Shi (ORCID: https://orcid.org/0000-0002-9204-9949)
- Xikai Liu (ORCID: https://orcid.org/0000-0002-9964-1873)
- Weikang Xue (ORCID: https://orcid.org/0009-0004-1082-3817)
- Robert B. Petersen (ORCID: https://orcid.org/0000-0002-3154-0072)
- Yanxun V. Yu (ORCID: https://orcid.org/0000-0001-6617-0166)
- Liangliang Song (ORCID: https://orcid.org/0000-0002-4536-0478)
- Li Xu (ORCID: https://orcid.org/0000-0001-5378-8020)
- Linwei Yu (ORCID: https://orcid.org/0000-0002-0287-4970)
- Ning Li (ORCID: https://orcid.org/0000-0002-9789-1633)
- Hong Chen (ORCID: https://orcid.org/0000-0003-3478-6139)
- Yu Zhang (ORCID: https://orcid.org/0000-0001-6751-9294)
- Ling Zheng (ORCID: https://orcid.org/0000-0002-6545-4180)
- Yuchen Chen (ORCID: https://orcid.org/0000-0001-8558-3062)
- Xinran Liu (ORCID: https://orcid.org/0000-0001-8559-591X)
- Xi Li
- Chen Wang (ORCID: https://orcid.org/0000-0002-2132-0869)
Institutions
- Union Hospital (HK)
- Central Michigan University (US)
- Wuhan University (CN)
- Zhongnan Hospital of Wuhan University (CN)
- Huazhong University of Science and Technology (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-10-09
- DOI
- https://doi.org/10.1038/s41467-024-53086-8
- Citations
- 31
- Primary Topic
- Nuclear Receptors and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 8.32
Funders
- National Natural Science Foundation of China
- Huazhong University of Science and Technology
- Natural Science Foundation of Hubei Province