Abstract
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-PGC1α 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.
Highlights
Huntington’s disease (HD) is a progressive neurological disorder that causes movement, cognitive, and behavioral problems in the central nervous system
The cause of HD is due to the mutation of a protein called huntingtin (Htt), which contains a sequence with an expansion of CAG repeats
It is known that the risk of developing diabetes in HD patients is approximately seven times that of the normal control group, suggesting mutant huntingtin (mHtt)-induced toxicity may be strongly associated with metabolic disorders [5]
Summary
Huntington’s disease (HD) is a progressive neurological disorder that causes movement, cognitive, and behavioral problems in the central nervous system. The accumulation of mHtt has been suggested to interfere with cellular functions including increased oxidative stress, axonal transport defects, impaired synaptic function, decreased autophagy, and eventually leading to neuron death These pathological changes are mainly found in the basal ganglia and cerebral cortex of HD patients, causing the dysfunction of the corticalbasal ganglia motor control circuit, thereby hindering the control of the patient’s voluntary movement [3]. It is known that the risk of developing diabetes in HD patients is approximately seven times that of the normal control group, suggesting mHtt-induced toxicity may be strongly associated with metabolic disorders [5]. Our previous study has reported that compounds increase insulin signaling can enhance protein clearance and reduce the mHtt-induced neurotoxicity in neuronal cells. We demonstrated that miR-302 was dramatically downregulated in mHtt-overexpressed neuronal cells, and this suppression may be one of the causes of neuronal insulin resistance in the pathogenesis of HD
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
