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

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 di...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2015-08, Vol.112 (31), p.9751-9756
Main Authors: Ahmed, Ishrat, Sbodio, Juan I., Harraz, Maged M., Tyagi, Richa, Grima, Jonathan C., Albacarys, Lauren K., Hubbi, Maimon E., Xu, Risheng, Kim, Seyun, Paul, Bindu D., Snyder, Solomon H.
Format: Article
Language:English
Subjects:
Adult
Aged
Animals
Biocatalysis
Biological Sciences
Cells
Demography
Dependovirus - metabolism
Disease Models, Animal
Enzyme Stability
Female
Humans
Huntington Disease - enzymology
Huntington Disease - genetics
Huntington Disease - pathology
Huntington Disease - physiopathology
Huntingtons disease
Kinases
Lipids
Male
Mice, Transgenic
Middle Aged
Mitochondria - metabolism
Motor Activity
Mutation
Neostriatum - enzymology
Neostriatum - pathology
Neostriatum - physiopathology
Neurons - metabolism
Neurons - pathology
Phosphotransferases (Alcohol Group Acceptor) - genetics
Phosphotransferases (Alcohol Group Acceptor) - metabolism
Postmortem Changes
Proto-Oncogene Proteins c-akt - metabolism
Repressor Proteins - metabolism
RNA, Messenger - genetics
RNA, Messenger - metabolism
Signal Transduction
Survival Analysis
Transcription, Genetic
Tumor Suppressor Proteins - metabolism
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1511810112