Akt is altered in an animal model of Huntington's disease and in patients

Abstract

The insulin-like growth factor I (IGF-1)/Akt pathway plays a crucial role in Huntington's disease by phosphorylating the causative protein, polyQ-huntingtin, and abolishing its toxic properties [Humbert et al. (2002)Dev. Cell, 2, 831-837; Rangone et al. (2004)Eur. J. Neurosci., 19, 273-279]. Therefore, dysregulation of this pathway may be essential for disease progression. In the present report, we thus aimed to analyse the status of Akt in brain or in peripheral tissues in Huntington's disease. Using a genetic model of Huntington's disease in rat that reproduces neuronal dysfunction and death, we show a progressive alteration of Akt during neuronal dysfunction and prior neurodegeneration. By analysing a limited number of lymphoblasts and lymphocytes, we detected modifications of Akt in Huntington's disease patients confirming a dysregulation of Akt in the disease process. Finally, we demonstrate that during late stages of the disease, Akt is cleaved into an inactive form by caspase-3. These observations demonstrate a progressive but marked alteration of this pro-survival pathway in Huntington's disease, and further implicate it as a key transduction pathway regulating the toxicity of huntingtin.

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

“…Reduced Akt was previously reported in HD patients, appearing as a shorter inactive caspase-3-cleaved form [27,75]. 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].…”

“…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].…”

Huntington’s disease: Neural dysfunction linked to inositol polyphosphate multikinase

“…PIP 3 physiologically activates Akt protein kinase. Akt signaling deficits have been described previously in HD striatum and lymphoblasts (24). We observe a 70% depletion of phospho-Akt levels in Q111 cells at the T308 and S473 sites ( Fig.…”

PH domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the PI3K/Akt pro-survival pathway in Huntington's disease striatum

“…37,38 Furthermore, in an acute rat model of HD showing massive cell death a decrease of pAkt levels occurs before neuronal loss. 39 Here we show that Akt is still activated at late stages of the disease and that these changes are occurring in striatal medium-sized spiny projection neurons, the most affected in HD. Therefore, our results suggest that increased Akt activation could counteract mhtt toxicity, raising the threshold above which apoptotic signals can occur.…”