The Neuroprotective Effect of miR-196a on Neuronal Morphology through Targeting IMP3

摘要

Huntington’s disease (HD) is an inherited neurodegenerative disease leading to motor control dysfunction and cognitive deficit in patients resulting from the neurotoxicity primarily in the central nervous system (CNS) along with altered gene expression Previously our research had found that overexpression of miR-196a ameliorated pathological phenotypes of HD models in vitro and in vivo and provided beneficial regulations for neuronal cytoskeleton We now elucidate the mechanism of the neuroprotective effects of miR-196a Bioinformatics predicts that insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3 or IMP3) is a potential target gene of miR-196a which is involved in cytoskeleton remodeling during malignant transformation in cancers Therefore we hypothesize that miR-196a may improve the neuronal morphology through targeting IMP3 Here we confirm that miR-196a inhibits the endogenous expression level of IMP3 in N2a cells by targeting the 3’UTR of IMP3 transcript Besides the endogenous IMP3 is suppressed in miR-196a transgenic mice We further show that miR-196a inhibits IMP3 in N2a cells differentiated by retinoic acid and in mouse primary cortical neurons and overexpression of IMP3 blocks the morphology protective effect of miR-196a Additionally the exogenous IMP3 restrains the neurite outgrowth and leads to abnormal morphology including decreased F-actin intensity and flattened cell shape Furthermore in screening the expression profiling of IMP3 in the R6/2 HD mouse model we find an ectopic expression pattern of IMP3 in their adult cortical tissues which is distinct from the wild type mice and correlated with disease progression These results implicate a detrimental role of elevated IMP3 in neuronal pathogenesis and miR-196a may provide beneficial effects for neuronal morphology through targeting IMP3 In future work we will study the role of IMP3 in the neuroprotective effect of miR-196a in HD models in vitro and in vivo We anticipate that this study will shed light on promising treatment strategies for HD

獎項日期	2018 8月 10
原文	English
監督員	Shang-Hsun Yang (Supervisor)