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

alpha-Synuclein (alpha-Syn) protein is implicated in the pathogenesis of Parkinson disease (PD). It is primarily cytosolic and interacts with cell membranes. alpha-Syn also occurs in the nucleus. Here we investigated the mechanisms involved in nuclear translocation of alpha-Syn. We analyzed alterations in gene expression following induced alpha-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 alpha-Syn binds RA and translocates to the nucleus to selectively enhance gene transcription. Nuclear translocation of alpha-Syn is regulated by calreticulin and is leptomycin-B independent. Importantly, nuclear translocation of alpha-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 alpha-Syn in the regulation of RA-mediated gene transcription and its toxicity in the synucleinopathies.