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 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.