title: Huntington's disease: Neural dysfunction linked to inositol polyphosphate multikinase.
abstract: Huntington's disease (HD) is a progressive neurodegenerative disease caused by a glutamine repeat expansion in mutant huntingtin (mHtt). Despite the known genetic cause of HD, the pathophysiology of this disease remains to be elucidated. Inositol polyphosphate multikinase (IPMK) is an enzyme that displays soluble inositol phosphate kinase activity, lipid kinase activity, and various noncatalytic interactions. We report a severe loss of IPMK in the striatum of HD patients and in several cellular and animal models of the disease. This depletion reflects mHtt-induced impairment of COUP-TF-interacting protein 2 (Ctip2), a striatal-enriched transcription factor for IPMK, as well as alterations in IPMK protein stability. IPMK overexpression reverses the metabolic activity deficit in a cell model of HD. IPMK depletion appears to mediate neural dysfunction, because intrastriatal delivery of IPMK abates the progression of motor abnormalities and rescues striatal pathology in transgenic murine models of HD.
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors.forename: Ishrat
authors.initials: I
authors.lastname: Ahmed
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors.forename: Juan I
authors.initials: JI
authors.lastname: Sbodio
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors.forename: Maged M
authors.initials: MM
authors.lastname: Harraz
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors.forename: Richa
authors.initials: R
authors.lastname: Tyagi
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Grima
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors.forename: Lauren K
authors.initials: LK
authors.lastname: Albacarys
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors.forename: Maimon E
authors.initials: ME
authors.lastname: Hubbi
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors.forename: Risheng
authors.initials: R
authors.lastname: Xu
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea;
authors.forename: Seyun
authors.initials: S
authors.lastname: Kim
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205; bpaul8@jhmi.edu ssnyder@jhmi.edu.
authors.forename: Bindu D
authors.initials: BD
authors.lastname: Paul
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205 bpaul8@jhmi.edu ssnyder@jhmi.edu.
authors.forename: Solomon H
authors.initials: SH
authors.lastname: Snyder
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D055162:Biocatalysis; D003710:Demography; D000229:Dependovirus / Q000378:metabolism; D004195:Disease Models, Animal; D004795:Enzyme Stability; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008822:Mice, Transgenic; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D009043:Motor Activity; D017072:Neostriatum / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D011180:Postmortem Changes; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C511143:Bcl11b protein, mouse; D012333:RNA, Messenger; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); C434257:inositol polyphosphate multikinase; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; Ctip2; Huntington's disease; IPMK; inositol polyphosphate multikinase