Autism-linked mutations impact liquid-liquid phase separation of synaptic proteins. Yi-Ping Hsueh, Kuo-Chiang Hsia, and Ting-Fang Wang from the Institute of Molecular Biology reveal for the first time that autism spectrum disorder (ASD)-linked mutations alter LLPS of synaptic proteins and that the zinc levels controlled by synaptic stimulation regulate the liquid-to-gel phase transition of ASD-related synaptic proteins. Cortactin-binding protein 2 (CTTNBP2), an ASD-linked protein, forms self-assembled condensates through its C-terminal intrinsically disordered region and facilitates SHANK3 co-condensation at dendritic spines. Zinc binds the N-terminal coiled-coil region of CTTNBP2, promoting higher-order assemblies. Consequently, it reduces CTTNBP2 mobility and enhances the stability and synaptic retention of CTTNBP2 condensates. Autism-linked mutations alter condensate formation and synaptic retention of CTTNBP2 and impair mouse social behaviors, which are all ameliorated by zinc supplementation. The study was published in Nature Communications on May 13, 2022.

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Autism, Zinc and Liquid-Liquid Phase Separation