Enhanced Akt Signaling Is an Early Pro-survival Response That Reflects N-Methyl-D-aspartate Receptor Activation in Huntington's Disease Knock-in Striatal Cells

Abstract

Huntington's disease features the loss of striatal neurons that stems from a disease process that is initiated by mutant huntingtin. Early events in the disease cascade, which predate overt pathology in Hdh CAG knock-in mouse striatum, implicate enhanced N-methyl-D-aspartate (NMDA) receptor activation, with excitotoxity caused by aberrant Ca 2؉ influx. Here we demonstrate in precise genetic Huntington's disease mouse and striatal cell models that these early phenotypes are associated with activation of the Akt pro-survival signaling pathway. Elevated levels of activated Ser (

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]. Another study demonstrated that p-(Ser473)Akt was unchanged in YAC128 and in R6/2 HD mice, but the levels of p-(Ser421)Htt were decreased in the striatum of YAC128 mice and in cells expressing mHtt [79].…”

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

“…To investigate whether altered PHLPP1 levels could be responsible for the previously reported accumulation of pAkt (Ser473) in knock-in HD models, 12 we looked at PHLPP1 protein levels in wild-type (STHdh Q7/Q7 ) and mutant (STHdh Q111/Q111 ) striatal cells, and in the striatum of 5-month-old wild-type (Hdh Q7/Q7 ) and mutant (Hdh Q111/Q111 ) knock-in mice. As shown in Figure 1, PHLPP1 protein levels were decreased in both STHdh Q111/Q111 cells and Hdh Q111/Q111 mouse striatum compared with their respective controls.…”

“…12 Thus, we next assessed whether reduced PHLPP1 protein levels in STHdh Q111/Q111 cells could affect the rate of Akt dephosphorylation when the activation signal is blocked. To this end, we treated STHdh Q7/Q7 and STHdh Q111/Q111 cells with wortmannin, a PI3K inhibitor, and pAkt (Ser473) levels were assessed at different time points.…”

“…Here, we also show that pAkt (Ser473) protein levels are increased in the striatum of the N-terminal exon-1 mouse models according to previous results obtained in knock-in models. 12 Higher and sustained pAkt (Ser473) levels in the striatum during the progression of the disease could be attributed in part to the reduction of PHLPP1 protein levels as both events occur simultaneously. Consistent with high levels of active Akt, the phosphorylation of GSK3b and FoxO1 was increased in the striatum of R6/1 mice.…”

“…14 In accordance, enhanced levels of phosphorylated Akt (pAkt) appear as an early striatal pro-survival response in the HD knock-in mouse model Hdh Q111 and in the cell model STHdh Q111/Q111 . 12 Cells maintain a dynamic steady state of pAkt, balanced by the activity of kinases and phosphatases. 15 Akt is activated through phosphorylation at Thr308 or Ser473 16 in response to the activation of the phosphatidylinositol 3-kinase (PI3K), and its signaling is acutely terminated by dephosphorylation.…”