Dataset Information

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

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

SUBMITTER: Davidi D

PROVIDER: S-EPMC7052517 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Davidi Dana D Schechter Meir M Elhadi Suaad Abd SA Matatov Adar A Nathanson Lubov L Sharon Ronit R

iScience 20200214 3

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 re ...[more]

PMID: 32120069

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Project description:BackgroundVitamin A is necessary for kidney development and has also been linked to regulation of solute and water homeostasis and to protection against kidney stone disease, infection, inflammation, and scarring. Most functions of vitamin A are mediated by its main active form, all-trans retinoic acid (tRA), which binds retinoic acid receptors (RARs) to modulate gene expression. We and others have recently reported that renal tRA/RAR activity is confined to the ureteric bud (UB) and collecting duct (CD) cell lineage, suggesting that endogenous tRA/RARs primarily act through regulating gene expression in these cells in embryonic and adult kidney, respectively.Methodology/principal findingsTo explore target genes of endogenous tRA/RARs, we employed the mIMCD-3 mouse inner medullary CD cell line, which is a model of CD principal cells and exhibits constitutive tRA/RAR activity as CD principal cells do in vivo. Combining antagonism of RARs, inhibition of tRA synthesis, exposure to exogenous tRA, and gene expression profiling techniques, we have identified 125 genes as candidate targets and validated 20 genes that were highly regulated (Dhrs3, Sprr1a, and Ppbp were the top three). Endogenous tRA/RARs were more important in maintaining, rather than suppressing, constitutive gene expression. Although many identified genes were expressed in UBs and/or CDs, their exact functions in this cell lineage are still poorly defined. Nevertheless, gene ontology analysis suggests that these genes are involved in kidney development, renal functioning, and regulation of tRA signaling.Conclusions/significanceA rigorous approach to defining target genes for endogenous tRA/RARs has been established. At the pan-genomic level, genes regulated by endogenous tRA/RARs in a CD cell line have been catalogued for the first time. Such a catalogue will guide further studies on molecular mediators of endogenous tRA/RARs during kidney development and in relation to renal defects associated with vitamin A deficiency.

Dataset Information

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

Publications

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

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