The Parkinson's disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability.

Cell
Authors
Keywords
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.

Year of Publication
2022
Journal
Cell
Volume
185
Issue
12
Pages
2035-2056.e33
Date Published
2022 06 09
ISSN
1097-4172
DOI
10.1016/j.cell.2022.05.008
PubMed ID
35688132
Links
Grant list
R21 NS112858 / NS / NINDS NIH HHS / United States
R01 MH101244 / MH / NIMH NIH HHS / United States
R35 GM127131 / GM / NIGMS NIH HHS / United States
R01 NS109209 / NS / NINDS NIH HHS / United States