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.
Highlights
Huntington’s disease (HD) is a progressive neurodegenerative disease that affects motor and cognitive functions and results in complete physical and mental deterioration
Given that GLP-1 is best known for its ability to facilitate insulin signaling, we investigated whether liraglutide, a GLP-1 analogue approved and widely used in the treatment of type-2 diabetes, protects against Mutant HTT (mHTT)-induced neurotoxicity
Our present observations suggest that mHTT overexpression leads to impaired insulin signaling and HTT aggregation
Summary
Huntington’s disease (HD) is a progressive neurodegenerative disease that affects motor and cognitive functions and results in complete physical and mental deterioration. Exon 1 of the normal HTT gene contains 10–35 CAG trinucleotide repeats, whereas that of mHTT may carry 36 or more expanded repeats and is associated with a pronounced HD phenotype [2]. The number of repeats is roughly correlated with disease severity and age at disease onset [3]. This association indicates that the size of the CAG repeat plays a critical role in the pathogenesis of HD. The exact neurotoxic mechanisms involved in mHTT-induced neurodegeneration have not yet been unraveled, the accumulation of mHTT affects various cellular functions and causes neurotoxicity [4]. MHTT aggregates cause the impairment of the autophagy-mediated degradation of misfolded proteins, thereby facilitating the initiation of mHTT aggregate accumulation [7]
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