ABSTRACT: 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, de Jager P, Myers CL, Lindquist S, Greenmyre TJ, Bartel DP, Feany MB, Sunyaev S, Chung CY and Khurana V. Alpha-synuclein, Syn, 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 Syn directly modulates Processing-bodies (P-bodies), membraneless organelles that function in mRNA turnover and storage. The N-terminus of alpha Syn, but not other synucleins, dictates mutually exclusive binding either to cellular membranes or to P-bodies in the cytosol. Syn binds directly to multiple decapping proteins in close proximity on the Edc4 scaffold. As Syn pathologically accumulates, aberrant interaction with Edc4 occurs at the expense of physiologic decapping-module interactions. mRNA-decay kinetics within PD-relevant pathways are consequently disrupted in PD patient neurons and brain. Genetic modulation of P-body components alters Syn toxicity, and human genetic analysis lends support to the disease-relevance of these interactions. Beyond revealing an unexpected aspect of Syn function and pathology, our data highlight the versatility of conformationally plastic proteins with high intrinsic disorder.
Steven A. Carr