Investigate the Protective Effects of miR-196a on Spinocerebellar Ataxia Type 3 via Modulating Mitochondrial Functions

摘要

Spinocerebellar ataxia type 3 (SCA3) the most common dominantly inherited SCA results from the expansion of polyglutamines (polyQ) in the ataxin-3 protein and leads to the formation of aggregates In addition to aggregates it has been proposed that the toxic polyQ protein may impair mitochondrial functions Until now there has been no effective therapy to delay SCA3 progression According to previous studies microRNAs (miRNAs) have played pivotal roles in neural diseases For example miRNA-196a (miR-196a) can provide beneficial effects in Huntington’s disease (HD) and Spinal-Bulbar Muscular Atrophy (SBMA) two polyQ diseases Because SCA3 is also a polyQ disease we hypothesize that miR-196a may improve the pathogenesis of SCA3 models In order to study the effects of miR-196a in SCA3 we establish SCA3 cell and mouse models first In the in vitro results we find that the truncated ataxin-3 (T101Q) leads to the formation of intranuclear aggregates and neuronal death in N2a mouse neuroblastoma cells In the in vivo results the SCA3 mouse models express abundant and pathological aggregates in the cerebellum Moreover when miR-196a is overexpressed in SCA3 cell models the T101Q and pathological aggregates are suppressed Furthermore miR-196a also decreases reactive oxygen species and improves the impairment of mitochondrial functions including reducing mitochondrial membrane potential and mitochondrial fission to lower neuronal death in SCA3 cell models Taken together these results show that the T101Q leads to abundant and pathological aggregates and the treatment of miR-196a ameliorates the aggregates reactive oxygen species impaired mitochondrial functions and neuronal death in SCA3 cell models Therefore miR-196a-mediated therapeutic methods can be utilized in this disease to provide protective effects

獎項日期	2015 8月 24
原文	English
監督員	Shang-Hsun Yang (Supervisor)