Allele-specific regulation of mutant Huntingtin by Wig1, a downstream target of p53

作者：Kim Sun Hong; Shahani Neelam; Bae Byoung Ii; Sbodio Juan I; Chung Youjin; Nakaso Kazuhiro; Paul Bindu D; Sawa Akira^*

来源：Human Molecular Genetics, 2016, 25(12): 2514-2524.

DOI：10.1093/hmg/ddw115

p53 has been implicated in the pathophysiology of Huntington's disease (HD). Nonetheless, the molecular mechanism of how p53 may play a unique role in the pathology remains elusive. To address this question at the molecular and cellular biology levels, we initially screened differentially expressed molecules specifically dependent on p53 in a HD animal model. Among the candidate molecules, wild-type p53-induced gene 1 (Wig1) is markedly upregulated in the cerebral cortex of HD patients. Wig1 preferentially upregulates the level of mutant Huntingtin (Htt) compared with wild-type Htt. This allele-specific characteristic of Wig1 is likely to be explained by higher affinity binding to mutant Htt transcripts than normal counterpart for the stabilization. Knockdown of Wig1 level significantly ameliorates mutant Htt-elicited cytotoxicity and aggregate formation. Together, we propose that Wig1, a key p53 downstream molecule in HD condition, play an important role in stabilizing mutant Htt mRNA and thereby accelerating HD pathology in the mHtt-p53-Wig1 positive feedback manner.

• 出版日期2016-6-15