Heat Shock Factor 1-Regulated miRNAs Can Target Huntingtin and Suppress Aggregates of Mutant Huntingtin.

Abstract

Heat shock factor 1 (HSF1) is the master regulator of chaperone network in mammalian cells and can protect cells from adverse effects of misfolded proteins by rapidly inducing expression of multiple heat shock proteins (HSPs) and other cytoprotective proteins. HSF1 also regulates transcription of microRNAs (miRNAs) in heat shock-dependent manner and these miRNAs are likely to regulate diverse cellular processes by acting as downstream effectors of HSF1. The study was aimed at understanding the effect of HSF1-regulated miRNAs on huntingtin expression and Huntington's Disease (HD) pathogenesis, if any. The cumulative effect of all HSF1-regulated miRNAs on huntingtin expression was measured by quantitative real-time PCR and luciferase reporter assay and effect of miRNAs on mutant huntingtin aggregates was determined by aggregate counting assay. Our study reveals that HSF1-regulated miRNAs cumulatively target huntingtin and reduce its expression in HD cell model. We also identify 4 huntingtin-targeting miRNAs viz. miR-125b, miR-146a, miR-150 and miR-214 as candidate miRNAs responsible for observed inhibitory effect of HSF1 on huntingtin expression. We further demonstrate that HSF1-regulated miRNAs together can suppress aggregates of mutant huntingtin in cell model of HD. We conclude that the protective effect of HSF1 in the context of HD is a consequence of synergistic induction of HSPs and HSF1-regulated huntingtin-targeting miRNAs. Moreover, the suppressive effect of HSF1-regulated miRNAs on mutant huntingtin aggregates indicates their potential as therapeutic agents for the treatment of HD.