| Literature DB >> 35688132 |
Erinc Hallacli1, Can Kayatekin2, Sumaiya Nazeen3, Xiou H Wang4, Zoe Sheinkopf4, Shubhangi Sathyakumar4, Souvarish Sarkar5, Xin Jiang6, Xianjun Dong7, Roberto Di Maio8, Wen Wang9, Matthew T Keeney8, Daniel Felsky10, Jackson Sandoe2, Aazam Vahdatshoar4, Namrata D Udeshi11, D R Mani11, Steven A Carr11, Susan Lindquist12, Philip L De Jager13, David P Bartel12, Chad L Myers9, J Timothy Greenamyre8, Mel B Feany5, Shamil R Sunyaev14, Chee Yeun Chung6, Vikram Khurana15.
Abstract
Alpha-synuclein (αS) 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 αS directly modulates processing bodies (P-bodies), membraneless organelles that function in mRNA turnover and storage. The N terminus of αS, but not other synucleins, dictates mutually exclusive binding either to cellular membranes or to P-bodies in the cytosol. αS associates with multiple decapping proteins in close proximity on the Edc4 scaffold. As αS 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 αS toxicity, and human genetic analysis lends support to the disease-relevance of these interactions. Beyond revealing an unexpected aspect of αS function and pathology, our data highlight the versatility of conformationally plastic proteins with high intrinsic disorder.Entities:
Keywords: Lewy body disease; Parkinson's disease; Processing bodies; RNA-binding proteins; alpha-synuclein; iPSC; mRNA degradation; mRNA stability; rare variant; synucleinopathy
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Year: 2022 PMID： 35688132 PMCID： PMC9394447 DOI： 10.1016/j.cell.2022.05.008
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 66.850