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

• Published in: Cell Vol. 185; no. 12; pp. 2035 - 2056.e33
• Main Authors: Hallacli, Erinc, Kayatekin, Can, Nazeen, Sumaiya, Wang, Xiou H., Sheinkopf, Zoe, Sathyakumar, Shubhangi, Sarkar, Souvarish, Jiang, Xin, Dong, Xianjun, Di Maio, Roberto, Wang, Wen, Keeney, Matthew T., Felsky, Daniel, Sandoe, Jackson, Vahdatshoar, Aazam, Udeshi, Namrata D., Mani, D.R., Carr, Steven A., Lindquist, Susan, De Jager, Philip L., Bartel, David P., Myers, Chad L., Greenamyre, J. Timothy, Feany, Mel B., Sunyaev, Shamil R., Chung, Chee Yeun, Khurana, Vikram
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.06.2022
• Subjects: alpha-synuclein; alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Humans; iPSC; Lewy body disease; mRNA degradation; mRNA stability; Parkinson Disease - metabolism; Parkinson's disease; Plastics; Processing Bodies; Proteins; rare variant; RNA Stability; RNA-binding proteins; synucleinopathy; synucleinopathy; mRNA degradation; Parkinson's disease; Lewy body disease; Processing bodies; iPSC; RNA-binding proteins; alpha-synuclein; rare variant; mRNA stability
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2022.05.008

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. [Display omitted] •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.