title: Inositol hexakisphosphate kinases induce cell death in Huntington disease.
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.
authors.affiliation: Department of Neurology, Tokai University School of Medicine, Kanagawa 259-1193, Japan. enagata@is.icc.u-tokai.ac.jp
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Nagata
authors.forename: Adolfo
authors.initials: A
authors.lastname: Saiardi
authors.forename: Hideo
authors.initials: H
authors.lastname: Tsukamoto
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Okada
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Itoh
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Satoh
authors.forename: Johbu
authors.initials: J
authors.lastname: Itoh
authors.forename: Russell L
authors.initials: RL
authors.lastname: Margolis
authors.forename: Shunya
authors.initials: S
authors.lastname: Takizawa
authors.forename: Akira
authors.initials: A
authors.lastname: Sawa
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Takagi
mesh_terms: D017209:Apoptosis; D002467:Cell Nucleus / Q000201:enzymology* / Q000648:ultrastructure; D003593:Cytoplasm / Q000201:enzymology / Q000648:ultrastructure; D004789:Enzyme Activation / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D006816:Huntington Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008214:Lymphocytes / Q000201:enzymology* / Q000648:ultrastructure; D010766:Phosphorylation / Q000235:genetics; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D010833:Phytic Acid / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism
chemical_list: D010833:Phytic Acid; D051057:Proto-Oncogene Proteins c-akt; D017856:Phosphotransferases (Phosphate Group Acceptor); C115134:IP6K1 protein, human