The role of miR-196a in the pathogenesis of Huntington's disease

Abstract

Huntington’s disease (HD) is an inherited autosomal-dominant neurodegenerative disease that is caused by expansion of CAG repeats in the exon 1 of the huntingtin gene The aggregation of mutant huntingtin (htt) proteins affects the central nervous system especially striatum resulting in motor dysfunctions and cognitive declines and at present there is no cure for HD Recent reports have indicated that transcriptional dysregulation plays a critical role in the pathogenesis of HD Several studies suggest that RNA interference (RNAi) is a good approach for gene therapy with regard to HD because RNAi can decrease the expression of mutant htt at the post-transcription level To date no studies have used a microRNA (miRNA) transgenic mouse model to investigate the effects of miRNA on HD Based on previous data obtained in our lab we found that miR-196a was abnormally expressed in a HD model Therefore the aim of this study is to investigate the role of miR-196a in HD Results from the in vitro study showed that overexpression of miR-196a reduced mutant htt expression and pathological aggregates in HD models of human embryonic kidney cells and mouse neuroblastoma cells Furthermore the results from the in vivo study showed that miR-196a not only alleviated pathological mutant htt aggregates such as nuclear intranuclear and neuropil aggregates in the striatum and cortex but also improved the late-stage motor functions in HD transgenic mice overexpressing miR-196a The beneficial effects of miR-196a in HD might be through the improvement of ubiquitin-proteasome systems (UPS) gliosis and phospho-calmodulin-dependent protein kinase II (p-CaMKII) Taken together our results suggest that miR-196a provides beneficial effects with regard to HD Understanding the actions of miR-196a in the progression of HD will provide further insights for the development of gene therapies for this disease

Date of Award	2015 Jan 28
Original language	English
Supervisor	Shang-Hsun Yang (Supervisor)