-Synuclein (-Syn) is a protein implicated in the pathogenesis of Parkinsons disease (PD). It is primarily cytosolic and reversibly interacts with cell membranes. -Syn also occurs in the nucleus, however, the mechanisms involved in its nuclear localization are poorly understood. We analyzed alterations in gene expression following induced -Syn expression in SH-SY5Y cells. Analysis for upstream regulators pointed at alterations in transcription activity of retinoic acid receptors (RAR)s and additional nuclear receptors. We show that -Syn binds RA and translocates to the nucleus to selectively enhance gene transcription. Nuclear translocation of -Syn is regulated by calreticulin, in a leptomycin-B independent mechanism. Importantly, nuclear translocation of -Syn following RA treatment enhances its toxicity in cultured neurons and the expression levels of PD-associated genes, among which are two familial PDassociated genes, ATPase cation transporting 13A2 (ATP13A2) and PTEN-induced kinase 1 (PINK1). The results link a physiological role for -Syn in the regulation of RAmediated gene transcription and its toxicity in the synucleinopathies. SOURCE: Lubov Nathanson (lnathanson@nova.edu) -  Nova Southeastern University

Pluto Bioinformatics

GSE145804: -Synuclein Translocates To The Nucleus To Activate Retinoic Acid- Dependent Gene Transcription