miR-302 Attenuates Mutant Huntingtin-Induced Cytotoxicity through Restoration of Autophagy and Insulin Sensitivity

Huntington's disease (HD) is an autosomal-dominant brain disorder caused by mutant huntingtin (mHtt). Although the detailed mechanisms remain unclear, the mutational expansion of polyglutamine in mHtt is proposed to induce protein aggregates and neuronal toxicity. Previous studies have shown that the decreased insulin sensitivity is closely related to mHtt-associated impairments in HD patients. However, how mHtt interferes with insulin signaling in neurons is still unknown. In the present study, we used a HD cell model to demonstrate that the miR-302 cluster, an embryonic stem cell-specific polycistronic miRNA, is significantly downregulated in mHtt-Q74-overexpressing neuronal cells. On the contrary, restoration of miR-302 cluster was shown to attenuate mHtt-induced cytotoxicity by improving insulin sensitivity, leading to a reduction of mHtt aggregates through the enhancement of autophagy. In addition, miR-302 also promoted mitophagy and stimulated Sirt1/AMPK-PGC1 alpha pathway thereby preserving mitochondrial function. Taken together, these results highlight the potential role of miR-302 cluster in neuronal cells, and provide a novel mechanism for mHtt-impaired insulin signaling in the pathogenesis of HD.