1. β-synuclein regulates the phase transitions and amyloid conversion of α-synuclein.
- Author
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Li X, Yu L, Liu X, Shi T, Zhang Y, Xiao Y, Wang C, Song L, Li N, Liu X, Chen Y, Petersen RB, Cheng X, Xue W, Yu YV, Xu L, Zheng L, Chen H, and Huang K
- Subjects
- Animals, Humans, Mutation, Lewy Body Disease metabolism, Lewy Body Disease genetics, Lewy Body Disease pathology, Caenorhabditis elegans Proteins metabolism, Caenorhabditis elegans Proteins genetics, Presynaptic Terminals metabolism, Longevity genetics, alpha-Synuclein metabolism, alpha-Synuclein genetics, Caenorhabditis elegans metabolism, Caenorhabditis elegans genetics, beta-Synuclein metabolism, beta-Synuclein genetics, Parkinson Disease metabolism, Parkinson Disease genetics, Amyloid metabolism, Phase Transition
- 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., (© 2024. The Author(s).) more...
- Published
- 2024
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