The Parkinson’s disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability
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nihms-1815371.pdf
Description
Accepted version
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3.04 MB
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Checksum (MD5)
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Author(s)
Hallacli, Erinc
Kayatekin, Can
Nazeen, Sumaiya
Wang, Xiou H
Sheinkopf, Zoe
Sathyakumar, Shubhangi
Sarkar, Souvarish
Jiang, Xin
Dong, Xianjun
Di Maio, Roberto
Date Issued
2022
Journal
Cell
Publisher
Elsevier BV
Citation
Hallacli, Erinc, Kayatekin, Can, Nazeen, Sumaiya, Wang, Xiou H, Sheinkopf, Zoe et al. 2022. "The Parkinson’s disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability." Cell, 185 (12).
Version
Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/J.CELL.2022.05.008
