The Role of Inositol Polyphosphate Multikinase in Huntington's Disease
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Huntington’s disease (HD) is a progressive neurodegenerative disorder characterized by several motor signs including chorea, rigidity, and bradykinesia, as well as cognitive and psychiatric symptoms. This disease is caused by a poly-glutamine repeat expansion in the N-terminal region of huntingtin (Htt) and mainly affects the striatum despite the ubiquitous expression of Htt. Several mechanisms have been suggested for the striatal specificity of HD ranging from changes in striatal-enriched proteins like Rhes to excitotoxicity from corticostriatal projections. The transcription factor Ctip2, which is preferentially expressed in the striatum, hippocampus, and cortical subplate, is also impaired in HD. Given the putative role of Ctip2 in the regulation of inositol polyphosphate multikinase (IPMK), we hypothesized that IPMK is involved in the pathophysiology of HD. IPMK is known for its various functions in regulating cell survival and death through soluble kinase and PI3-kinase activities, which produce the inositol phosphates IP4 and IP5, and the phosphatidylinositol PIP3, respectively. IPMK also displays various non-catalytic interactions, including the regulation of mTOR signaling and CBP/p300-mediated transcription. We have detected a significant loss of IPMK in post-mortem HD striatal tissues and various cellular and animal models of the disease. The depletion of IPMK protein and mRNA result from mutant Htt-induced impairment of Ctip2, as well as alterations in IPMK protein stability. Overexpression of IPMK rescues the mitochondrial metabolic activity deficit in a cellular model of HD. This rescue requires the lipid kinase activity of IPMK and implicates the Akt signaling pathway downstream of IPMK signaling in HD. More importantly, viral delivery of IPMK in the striatum improves striatal pathology and motor performance of a transgenic mouse model of HD. Our findings indicate that IPMK is an important player in the pathophysiology of HD. Furthermore, this Ctip2/IPMK/Akt signaling pathway provides a novel therapeutic target and approach to enhancing Akt signaling in HD and potentially other neurodegenerative diseases.