GLP-1 Analogue Liraglutide Attenuates Mutant Huntingtin-Induced Neurotoxicity by Restoration of Neuronal Insulin Signaling

Abstract

Huntington's disease (HD) is a progressive and fatal neurodegenerative disease caused by CAG repeat expansion in the coding region of huntingtin (HTT) protein. The accumulation of mutant HTT (mHTT) contributes to neurotoxicity by causing autophagy defects and oxidative stress that ultimately lead to neuronal death. Interestingly, epidemiologic studies have demonstrated that the prevalence of type-2 diabetes, a metabolic disease mainly caused by defective insulin signaling, is higher in patients with HD than in healthy controls. Although the precise mechanisms of mHTT-mediated toxicity remain unclear, the blockade of brain insulin signaling may initiate or exacerbate mHTT-induced neurodegeneration. In this study, we used an in vitro HD model to investigate whether neuronal insulin signaling is involved in mHTT-mediated neurotoxicity. Our results demonstrated that mHTT overexpression significantly impairs insulin signaling and causes apoptosis in neuronal cells. However, treatment with liraglutide, a GLP-1 analogue, markedly restores insulin sensitivity and enhances cell viability. This neuroprotective effect may be attributed to the contribution of the upregulated expression of genes associated with endogenous antioxidant pathways to oxidative stress reduction. In addition, liraglutide stimulates autophagy through AMPK activation, which attenuates the accumulation of HTT aggregates within neuronal cells. Our findings collectively suggest that liraglutide can rescue impaired insulin signaling caused by mHTT and that GLP-1 may potentially reduce mHTT-induced neurotoxicity in the pathogenesis of HD.

Glucagon-like peptide 1 (GLP-1)

“…The neurotoxicity and neurodegeneration induced by the mutant HTT protein has been attributed to enhanced oxidative stress and accumulation of HTT due to inappropriate autophagic HTT clearance [829]. The prevalence of T2DM is elevated in patients with HD [830], suggesting that impaired insulin sensitivity might be a causal factor contributing to neurodegeneration in HD patients [830,831]. Overexpression of mutant HTT impairs insulin signaling and stimulates neuronal apoptosis in human SK-N-MC neuronal cells [831].…”

“…The prevalence of T2DM is elevated in patients with HD [830], suggesting that impaired insulin sensitivity might be a causal factor contributing to neurodegeneration in HD patients [830,831]. Overexpression of mutant HTT impairs insulin signaling and stimulates neuronal apoptosis in human SK-N-MC neuronal cells [831]. Treatment of SK-N-MC cells with liraglutide improves insulin sensitivity and enhances cell viability, potentially by mechanisms that include amelioration of neuronal glucotoxicity, improvement of oxidative stress and less aggregation of the mutant HTT through stimulation of AMPK-mediated autophagy [831].…”

Glucagon-like Peptide-1 (GLP-1)

“…The neurotoxicity and neurodegeneration induced by the mutant HTT protein has been attributed to enhanced oxidative stress and accumulation of HTT due to inappropriate autophagic HTT clearance [829]. The prevalence of T2DM is elevated in patients with HD [830], suggesting that impaired insulin sensitivity might be a causal factor contributing to neurodegeneration in HD patients [830,831]. Overexpression of mutant HTT impairs insulin signaling and stimulates neuronal apoptosis in human SK-N-MC neuronal cells [831].…”

“…The prevalence of T2DM is elevated in patients with HD [830], suggesting that impaired insulin sensitivity might be a causal factor contributing to neurodegeneration in HD patients [830,831]. Overexpression of mutant HTT impairs insulin signaling and stimulates neuronal apoptosis in human SK-N-MC neuronal cells [831]. Treatment of SK-N-MC cells with liraglutide improves insulin sensitivity and enhances cell viability, potentially by mechanisms that include amelioration of neuronal glucotoxicity, improvement of oxidative stress and less aggregation of the mutant HTT through stimulation of AMPKmediated autophagy [831].…”

“…Overexpression of mutant HTT impairs insulin signaling and stimulates neuronal apoptosis in human SK-N-MC neuronal cells [831]. Treatment of SK-N-MC cells with liraglutide improves insulin sensitivity and enhances cell viability, potentially by mechanisms that include amelioration of neuronal glucotoxicity, improvement of oxidative stress and less aggregation of the mutant HTT through stimulation of AMPKmediated autophagy [831]. Alzheimer's disease (AD) is characterized by neurodegeneration of cholinergic neurons in the hippocampus.…”