Hallacli E, Kayatekin C, Nazeen S, Wang XH, Sheinkopf Z, Sathyakumar S, Sarkar S, Jiang X, Dong X, Di Maio R, Wang W, Keeney MT, Felsky D, Sandoe J, Vahdatshoar A, Udeshi ND, Mani DR, Carr SA, Lindquist S, De Jager PL, Bartel DP, Myers CL, Greenamyre JT, Feany MB, Sunyaev SR, Chung CY, Khurana V

Alpha-synuclein (?S) is a conformationally plastic protein that reversibly binds to cellular membranes. It aggregates and is genetically linked to Parkinson's disease (PD). Here, we show that ?S directly modulates processing bodies (P-bodies), membraneless organelles that function in mRNA turnover and storage. The N terminus of ?S, but not other ...

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synucleins, dictates mutually exclusive binding either to cellular membranes or to P-bodies in the cytosol. ?S associates with multiple decapping proteins in close proximity on the Edc4 scaffold. As ?S pathologically accumulates, aberrant interaction with Edc4 occurs at the expense of physiologic decapping-module interactions. mRNA decay kinetics within PD-relevant pathways are correspondingly disrupted in PD patient neurons and brain. Genetic modulation of P-body components alters ?S toxicity, and human genetic analysis lends support to the disease-relevance of these interactions. Beyond revealing an unexpected aspect of ?S function and pathology, our data highlight the versatility of conformationally plastic proteins with high intrinsic disorder.

Date: Jun. 09, 2022

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