文章基本信息

标题：α-Synuclein Translocates to the Nucleus to Activate Retinoic-Acid-Dependent Gene Transcription
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作者：Dana Davidi ; Meir Schechter ; Suaad Abd Elhadi 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2020
卷号：23
期号：3
页码：1-42
DOI：10.1016/j.isci.2020.100910
语种：English
出版社：Elsevier
摘要：Summaryα-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.Graphical AbstractDisplay OmittedHighlights•α-Syn normally binds RA and translocates to the nucleus to regulate transcription•Nuclear translocation of α-Syn is regulated by calreticulin and Ca2+•Nuclear translocation of α-Syn is linked to PDMolecular Biology; Molecular Mechanism of Gene Regulation; Molecular Interaction; Molecular Neuroscience; Cell Biology