Title:Heat Shock Factor 1-Regulated miRNAs Can Target Huntingtin and Suppress Aggregates of Mutant Huntingtin
Volume: 4
Issue: 3
Author(s): Srijit Das and Nitai Pada Bhattacharyya
Affiliation:
Keywords:
Aggregates, heat shock factor 1, Huntington’s Disease, Huntingtin, microRNA.
Abstract: Background: 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. Methods: 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. Results: 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. Conclusion: 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.
