title: Allele-specific regulation of mutant Huntingtin by Wig1, a downstream target of p53.
abstract: 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.
authors.affiliation: Department of Psychiatry and Behavioral Sciences.
authors.forename: Sun-Hong
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Psychiatry and Behavioral Sciences.
authors.forename: Neelam
authors.initials: N
authors.lastname: Shahani
authors.affiliation: Neuroscience Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Byoung-Ii
authors.initials: BI
authors.lastname: Bae
authors.affiliation: Neuroscience Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Juan I
authors.initials: JI
authors.lastname: Sbodio
authors.affiliation: Department of Psychiatry and Behavioral Sciences.
authors.forename: Youjin
authors.initials: Y
authors.lastname: Chung
authors.affiliation: Division of Medical Biochemistry, Department of Pathophysiological and Therapeutic Science, Tottori University Faculty of Medicine, 86, Nishicho, Yonago, 683-8503, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakaso
authors.affiliation: Neuroscience Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Bindu D
authors.initials: BD
authors.lastname: Paul
authors.affiliation: Department of Psychiatry and Behavioral Sciences, asawa1@jhmi.edu.|Neuroscience Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Akira
authors.initials: A
authors.lastname: Sawa
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000818:Animals; D001344:Autopsy; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D002540:Cerebral Cortex / Q000378:metabolism / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics*; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D050505:Mutant Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; C086055:HTT protein, human; D000071058:Huntingtin Protein; D050505:Mutant Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; C436503:ZMAT3 protein, human