Inositol hexakisphosphate kinases induce cell death in Huntington disease |
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Authors: | Nagata Eiichiro Saiardi Adolfo Tsukamoto Hideo Okada Yoshinori Itoh Yoshiko Satoh Tadayuki Itoh Johbu Margolis Russell L Takizawa Shunya Sawa Akira Takagi Shigeharu |
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Institution: | Department of Neurology, Tokai University School of Medicine, Kanagawa 259-1193, Japan. enagata@is.icc.u-tokai.ac.jp |
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Abstract: | Inositol pyrophosphate diphosphoinositol pentakisphosphate is ubiquitously present in mammalian cells and contains highly energetic pyrophosphate bonds. We have previously reported that inositol hexakisphosphate kinase type 2 (InsP(6)K2), which converts inositol hexakisphosphate to inositol pyrophosphate diphosphoinositol pentakisphosphate, mediates apoptotic cell death via its translocation from the nucleus to the cytoplasm. Here, we report that InsP(6)K2 is localized mainly in the cytoplasm of lymphoblast cells from patients with Huntington disease (HD), whereas this enzyme is localized in the nucleus in control lymphoblast cells. The large number of autophagosomes detected in HD lymphoblast cells is consistent with the down-regulation of Akt in response to InsP(6)K2 activation. Consistent with these observations, the overexpression of InsP(6)Ks leads to the depletion of Akt phosphorylation and the induction of cell death. These results suggest that InsP(6)K2 activation is associated with the pathogenesis of HD. |
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Keywords: | Akt/PKB Apoptosis Autophagy Huntington Disease Inositol Phosphates |
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