Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 31, Pages 9751-9756Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1511810112
Keywords
Huntington's disease; inositol polyphosphate multikinase; IPMK; Ctip2; Akt
Categories
Funding
- US Public Health Service [MH-18501]
- CHDI Foundation
- Medical Scientist Training Grant [T32 GM007309]
- National Science Foundation Graduate Research Fellowship Award
- Thomas Shortman Training Fund Graduate Scholarship
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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.
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