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.

Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington’s disease knock-in striatal cells

“…Corroborating our study, p-(Ser473)Akt/Akt levels were significant decreased in STHdh Q111/Q111 cells [76], in HEK293 cells expressing mHtt with 68 CAG repeats [77] and in HD patient's lymphoblasts and lymphocytes [75]. Akt activation is an early pro-survival striatal response in knock-in Hdh Q111 mice and STHdh Q111/Q111 cells [28]; importantly, activation of IGF-1/Akt pathway caused Htt phosphorylation at Ser421, decreasing mHtt nuclear inclusions and mHtt toxicity [27] and regulated anterograde and retrograde transport defects in HD cortical neurons [78].…”

Inositol pyrophosphates inhibit synaptotagmin-dependent exocytosis

“…Finally, an imbalance in IP levels in the human body, as well as genetic deletion of IP6K enzymes in mouse models, has been implicated in a number of psychiatric and neurodegenerative diseases (47)(48)(49)(50). It will be important to gain insights into the structural mechanism underlying high-affinity 5-IP 7 binding and inhibition of the Syt1 protein.…”

New Horizons in Cellular Regulation by Inositol Polyphosphates: Insights from the Pancreaticβ-Cell

“…As we have mentioned above, a new study advocates a correlation between cellular distribution of IP6K2 in lymphoblasts and the HD phenotype (Nagata et al, 2011). In fact, the suggestion is that the residence of IP6K2 in the cytosol, which leads to an increase in basal 5-PP-InsP 5 , drives the autophagy phenotype seen in this disease.…”

“…It is possible that cytosolic IP6K2 is invisible to antibodies until it is released from its partner, which would be one way of combining the two sets of disparate data. Very recently, insights from studying IP6K2 in lymphoblast cells from patients with Huntingtons's disease suggest that IP6K2 is in the nucleus under normal conditions, but in the cytosol during the disease state (Nagata et al, 2011). We return to this disease model later, but these new data allow us to speculate that the location of an active IP6K2 in the cytosol, and not the nucleus, may reflect a pathologic phenotype of the ovarian cancer cells used in the original studies (Morrison et al, 2001(Morrison et al, , 2002 and may be another explanation for the discrepancy between the data from the two groups.…”