Transcriptional Regulation of the Beta-Synuclein 59-Promoter Metal Response Element by Metal Transcription Factor-1

The progression of many human neurodegenerative disorders is associated with an accumulation of alpha-synuclein. Alphasynuclein belongs to the homologous synuclein family, which includes beta-synuclein. It has been proposed that betasynuclein may be a natural regulator of alpha-synuclein. Therefore controlling beta-synuclein expression may control the accumulation of alpha-synuclein and ultimately prevent disease progression. The regulation of synucleins is poorly understood. We investigated the transcriptional regulation of beta-synuclein, with the aim of identifying molecules that differentially control beta-synuclein expression levels. To investigate transcriptional regulation of beta-synuclein, we used reporter gene assays and bioinformatics. We identified a region 21.1/20.6 kb upstream of the beta-synuclein translational start site to be a key regulatory region of beta-synuclein 59-promoter activity in human dopaminergic cells (SH-SY5Y). Within this key promoter region we identified a metal response element pertaining to a putative Metal Transcription Factor-1 (MTF1) binding site. We demonstrated that MTF-1 binds to this 59-promoter region using EMSA analysis. Moreover, we showed that MTF-1 differentially regulates beta-synuclein promoter binding site, as well as beta-synuclein mRNA and protein expression. This effect of MTF-1 on expression was found to be specific to beta-synuclein when compared to alphasynuclein. Understanding the regulation of synucleins and how they interact may point to molecular targets that could be manipulated for therapeutic benefit. In this study we showed that MTF-1 differentially controls the expression of betasynuclein when compared to its homolog alpha-synuclein. This could potentially provide a novel targets or pathways for therapeutic intervention and/or treatment of synucleinopathies. Citation: McHugh PC, Wright JA, Brown DR (2011) Transcriptional Regulation of the Beta-Synuclein 59-Promoter Metal Response Element by Metal Transcription Factor-1. PLoS ONE 6(2): e17354. doi:10.1371/journal.pone.0017354 Editor: Harm Kampinga, University Medical Center Groningen, University of Groningen, Netherlands Received December 13, 2010; Accepted January 29, 2011; Published February 28, 2011 Copyright: ß 2011 McHugh et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by Alzheimer’s Research Trust/PG2007/1. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected]