The Parkinson’s disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability
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 a...
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Published in | Cell Vol. 185; no. 12; pp. 2035 - 2056.e33 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Inc
09.06.2022
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Subjects | |
Online Access | Get full text |
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Summary: | 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.
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•αS toxicity linked to P-bodies through yeast, fly, and human genetics•Physiologic binding of αS N terminus to either membranes or P-body decapping module•Pathologic αSyn accumulation disrupts the decapping module in PD neurons and brain•Pathologic αSyn disrupts mRNA stability in PD iPSC neurons
Alpha-synuclein modulates mRNA stability to regulate gene expression with implications for understanding both normal cellular physiology and vulnerability to Parkinson’s disease and related disorders. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Deceased. Author Contributions EH, CK, VK conceived of and designed the project. EH and VK wrote the manuscript with input from authors. EH conducted and analyzed all biochemical and cell-based assays with help from ZS, XHW, SS, AV. CK and EH conducted yeast assays. VK, CYC and XJ oversaw iPSC reprogramming and genetic corrections with help from Ping Xu. JS constructed the Ngn2 piggyBac plasmid and cell lines were generated by AV. XD analyzed sequencing data for the mRNA stability experiment. DF, PLD conducted the ROSMAP analysis. WW, CM conducted the BridGE analysis. RDM, MK and TJG conducted brain PLA. SN, SRS designed and conducted RVTT analysis. SS and MBF conducted the Drosophila experiments. CYC designed and conducted the SILAC experiments with NDU, DRM and SAC performing the mass spectrometry and downstream analysis. EH prepared all the figures and analyzed the data with input from VK (except as otherwise noted). |
ISSN: | 0092-8674 1097-4172 |
DOI: | 10.1016/j.cell.2022.05.008 |