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

Erinc Hallacli; Can Kayatekin; Sumaiya Nazeen; Xiou H Wang; Zoe Sheinkopf; Shubhangi Sathyakumar; Souvarish Sarkar; Xin Jiang; Xianjun Dong; Roberto Di Maio; Wen Wang; Matthew T Keeney; Daniel Felsky; Jackson Sandoe; Aazam Vahdatshoar; Namrata D Udeshi; D R Mani; Steven A Carr; Susan Lindquist; Philip L De Jager; David P Bartel; Chad L Myers; J Timothy Greenamyre; Mel B Feany; Shamil R Sunyaev; Chee Yeun Chung; Vikram Khurana

doi:10.1016/j.cell.2022.05.008

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

Cell. 2022 Jun 9;185(12):2035-2056.e33. doi: 10.1016/j.cell.2022.05.008.

Authors

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

Affiliations

¹ Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Movement Disorders, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
² Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
³ Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Movement Disorders, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115.
⁴ Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Movement Disorders, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
⁵ Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
⁶ Yumanity Therapeutics, Boston, MA 02135, USA.
⁷ Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Genomics and Bioinformatics Hub, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA.
⁸ Pittsburgh Institute for Neurodegenerative Diseases and Department of Neurology, Pittsburgh, PA 15213, USA.
⁹ Department of Computer Science and Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
¹⁰ Krembil Centre for Neuroinformatics and Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada; Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, 155 College Street, Toronto, ON M5T 3M7, Canada.
¹¹ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹² Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Cambridge, MA 02142, USA; Department of Biology, MIT, Cambridge, MA 02139, USA.
¹³ Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY 10032, USA.
¹⁴ Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115.
¹⁵ Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Movement Disorders, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: [email protected].

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.

Keywords: Lewy body disease; Parkinson's disease; Processing bodies; RNA-binding proteins; alpha-synuclein; iPSC; mRNA degradation; mRNA stability; rare variant; synucleinopathy.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural

MeSH terms

Humans
Parkinson Disease* / metabolism
Processing Bodies
RNA Stability
alpha-Synuclein* / genetics
alpha-Synuclein* / metabolism

Substances

EDC4 protein, human
alpha-Synuclein

Abstract

Publication types

MeSH terms

Substances

Grants and funding