Transcriptional regulation of the beta-synuclein 5'-promoter metal response element by metal transcription factor-1.

Abstract

The progression of many human neurodegenerative disorders is associated with an accumulation of alpha-synuclein. Alpha-synuclein belongs to the homologous synuclein family, which includes beta-synuclein. It has been proposed that beta-synuclein 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 -1.1/-0.6 kb upstream of the beta-synuclein translational start site to be a key regulatory region of beta-synuclein 5'-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 (MTF-1) binding site. We demonstrated that MTF-1 binds to this 5'-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 alpha-synuclein. 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 beta-synuclein when compared to its homolog alpha-synuclein. This could potentially provide a novel targets or pathways for therapeutic intervention and/or treatment of synucleinopathies.

• Authors: Patrick C McHugh, Josephine A Wright, David R Brown
• Journal: PloS one (PLoS One) Vol. 6 Issue 2 Pg. e17354 (Feb 28 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21386983 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5' Untranslated Regions
• DNA-Binding Proteins
• Metals
• Transcription Factors
• beta-Synuclein
• transcription factor MTF-1

Topics

• 5' Untranslated Regions (genetics)
• Binding Sites (genetics)
• Cells, Cultured
• DNA-Binding Proteins (metabolism, physiology)
• Electrophoretic Mobility Shift Assay
• Gene Expression Regulation (drug effects, genetics)
• Humans
• Metals (pharmacology)
• Mutagenesis, Site-Directed
• Promoter Regions, Genetic (drug effects)
• Protein Binding (physiology)
• Response Elements (drug effects)
• Transcription Factors (metabolism, physiology)
• Transcriptional Activation (drug effects)
• beta-Synuclein (genetics, metabolism)