α-Synuclein Translocates to the Nucleus to Activate Retinoic-Acid-Dependent Gene Transcription

Dana Davidi; Meir Schechter; Suaad Abd Elhadi; Adar Matatov; Lubov Nathanson; Ronit Sharon

doi:10.1016/j.isci.2020.100910

α-Synuclein Translocates to the Nucleus to Activate Retinoic-Acid-Dependent Gene Transcription

iScience. 2020 Mar 27;23(3):100910. doi: 10.1016/j.isci.2020.100910. Epub 2020 Feb 14.

Authors

Dana Davidi¹, Meir Schechter¹, Suaad Abd Elhadi¹, Adar Matatov¹, Lubov Nathanson², Ronit Sharon³

Affiliations

¹ Biochemistry and Molecular Biology, IMRIC, The Hebrew University-Hadassah Medical School, Ein Kerem, 9112001 Jerusalem, Israel.
² Institute for Neuro Immune Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, USA.
³ Biochemistry and Molecular Biology, IMRIC, The Hebrew University-Hadassah Medical School, Ein Kerem, 9112001 Jerusalem, Israel. Electronic address: ronitsh@ekmd.huji.ac.il.

Abstract

α-Synuclein (α-Syn) protein is implicated in the pathogenesis of Parkinson disease (PD). It is primarily cytosolic and interacts with cell membranes. α-Syn also occurs in the nucleus. Here we investigated the mechanisms involved in nuclear translocation of α-Syn. We analyzed alterations in gene expression following induced α-Syn expression in SH-SY5Y cells. Analysis of upstream regulators pointed at alterations in transcription activity of retinoic acid receptors (RARs) and additional nuclear receptors. We show that α-Syn binds RA and translocates to the nucleus to selectively enhance gene transcription. Nuclear translocation of α-Syn is regulated by calreticulin and is leptomycin-B independent. Importantly, nuclear translocation of α-Syn following RA treatment enhances its toxicity in cultured neurons and the expression levels of PD-associated genes, including ATPase cation transporting 13A2 (ATP13A2) and PTEN-induced kinase1 (PINK1). The results link a physiological role for α-Syn in the regulation of RA-mediated gene transcription and its toxicity in the synucleinopathies.

Keywords: Cell Biology; Molecular Biology; Molecular Interaction; Molecular Mechanism of Gene Regulation; Molecular Neuroscience.