The IGF-1/Akt Pathway Is Neuroprotective in Huntington's Disease and Involves Huntingtin Phosphorylation by Akt

Abstract

In the search for neuroprotective factors in Huntington's disease, we found that insulin growth factor 1 via activation of the serine/threonine kinase Akt/PKB is able to inhibit neuronal death specifically induced by mutant huntingtin containing an expanded polyglutamine stretch. The IGF-1/Akt pathway has a dual effect on huntingtin-induced toxicity, since activation of this pathway also results in a decrease in the formation of intranuclear inclusions of mutant huntingtin. We demonstrate that huntingtin is a substrate of Akt and that phosphorylation of huntingtin by Akt is crucial to mediate the neuroprotective effects of IGF-1. Finally, we show that Akt is altered in Huntington's disease patients. Taken together, these results support a potential role of the Akt pathway in Huntington's disease.

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]. 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].…”

Characterization of hereditary inclusion body myopathy myoblasts: possible primary impairment of apoptotic events

“…Insulin-like growth factor-I (IGF-I) signaling is involved in muscle atrophy and degeneration, 28,29 and in the pathogenesis of various neurodegenerative disorders, including s-IBM. [30][31][32][33] Therefore, we evaluated the expression of two major antiapoptotic signaling molecules, activated downstream to IGF receptor: MAPK (extracellularly regulated kinase 1/2 (ERK1/2)), activated via Ras-Raf and Akt/PKB (protein kinase B), activated via phosphatidylinositol 3-kinase (PI3K). 34 The ERK1/2 cascade promotes cellular proliferation, survival and growth, through processes of DNA synthesis and cell-cycle progression.…”

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

“…mHtt is phosphorylated at S421 by Akt, and its dephosphorylation depends on the phosphatases PP1/ PP2A 107,108 , whereas APP is phosphorylated by Cdk5 and Gsk3β in neurons 104 (Suppl Table S3). Gsk3β is also the major kinase phosphorylating Tau in AD, which leads to the formation of insoluble Tau aggregates (Tau tangles) and subsequent disruption of the microtubule system 67 .…”