Huntington's disease: Neural dysfunction linked to inositol polyphosphate multikinase

被引：33

作者：

Ahmed, Ishrat ^{[1
]}

Sbodio, Juan I. ^{[1
]}

Harraz, Maged M. ^{[1
]}

Tyagi, Richa ^{[1
]}

Grima, Jonathan C. ^{[1
]}

Albacarys, Lauren K. ^{[1
]}

Hubbi, Maimon E. ^{[2
]}

Xu, Risheng ^{[1
]}

Kim, Seyun ^{[3
]}

Paul, Bindu D. ^{[1
]}

Snyder, Solomon H. ^{[1
,4
,5
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA

[2] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA

[3] Korea Adv Inst Sci & Technol, Dept Biol Sci, Taejon 305701, South Korea

[4] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA

[5] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2015年 / 112卷 / 31期

基金：

美国国家科学基金会;

关键词：

Huntington's disease; inositol polyphosphate multikinase; IPMK; Ctip2; Akt; ACTIVATED PROTEIN-KINASE; MUTANT-HUNTINGTIN; GENE; PHOSPHORYLATION; TRANSCRIPTION; NEURODEGENERATION; COACTIVATOR; NEURONS; AKT; EXPRESSION;

D O I：

10.1073/pnas.1511810112

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：9751 / 9756

页数：6

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