Inositol hexakisphosphate kinases induce cell death in Huntington disease

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 ₆K2), 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 ₆K2 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 ₆K2 activation. Consistent with these observations, the overexpression of InsP ₆Ks leads to the depletion of Akt phosphorylation and the induction of cell death. These results suggest that InsP ₆K2 activation is associated with the pathogenesis of HD.