1 GLP-1 analogue Liraglutide attenuates mutant 2 huntingtin-induced neurotoxicity by restoration of 3 neuronal insulin signaling 4

Huntington's disease (HD) is a progressive and fatal neurodegenerative disease caused 17 by CAG repeat expansion in the coding region of huntingtin (HTT) protein. The accumulation of 18 mutant HTT (mHTT) contributes to neurotoxicity by causing autophagy defects and oxidative stress 19 that ultimately lead to neuronal death. Interestingly, epidemiologic studies have demonstrated that 20 the prevalence of type-2 diabetes, a metabolic disease mainly caused by defective insulin signaling, 21 is higher in patients with HD than in healthy controls. Although the precise mechanisms of mHTT22 mediated toxicity remain unclear, the blockade of brain insulin signaling may initiate or exacerbate 23 mHTT-induced neurodegeneration. In this study, we used an in vitro HD model to investigate 24 whether neuronal insulin signaling is involved in mHTT-mediated neurotoxicity. Our results 25 demonstrated that mHTT overexpression significantly impairs insulin signaling and causes 26 apoptosis in neuronal cells. However, treatment with liraglutide, a GLP-1 analogue, markedly 27 restores insulin sensitivity and enhances cell viability. This neuroprotective effect may be attributed 28 to the contribution of the upregulated expression of genes associated with endogenous antioxidant 29 pathways to oxidative stress reduction. In addition, liraglutide stimulates autophagy through 30 AMPK activation, which attenuates the accumulation of HTT aggregates within neuronal cells. Our 31 findings collectively suggest that liraglutide can rescue impaired insulin signaling caused by mHTT 32 and that GLP-1 may potentially reduce mHTT-induced neurotoxicity in the pathogenesis of HD. 33