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.

Insulin Signaling Impairment in the Brain as a Risk Factor in Alzheimer’s Disease

“…The PI3k-Akt/PKB-mTOR pathway is also activated, compensating for the loss of insulin signaling (Hölscher, 2018). AMPk is also activated by the receptors (Chang et al, 2018). GLP-1 enhances insulin release making it an attractive treatment for T2DM (Baggio and Drucker, 2007; Doyle and Egan, 2007; Long-Smith et al, 2013).…”

“…Liraglutide reduced insulin de-sensitization and reduced the inflammation response caused by the injection of amyloid oligomers into the brains of cynomologous monkeys (Lourenco et al, 2013; Batista et al, 2018). GLP-1 mimetics protect mitochondrial activity and enhance mitochondrial genesis by reducing apoptotic BAX/BAD signaling and by increasing pro-mitochondrial Bcl-2 and PGC-1a signaling (Li et al, 2016a; Shi et al, 2017; Chang et al, 2018; Wang et al, 2018). Importantly, GLP-1 mimetics protect against ER stress and normalize autophagy impairments found in neurodegenerative disorders, which can explain how amyloid or tau aggregates are removed by the activation of the GLP-1 receptor (Sharma et al, 2013; Panagaki et al, 2017).…”

miR-302 Attenuates Mutant Huntingtin-Induced Cytotoxicity through Restoration of Autophagy and Insulin Sensitivity

“…To establish a cellular model for HD and evaluate the neurotoxic effects of poly-Q mutant huntingtin (mHtt), the human SK-N-MC neuronal cells were transfected with vectors encoding normal Htt (Htt-Q23) or mHtt (Htt-Q74) as previously described [8]. At 48 h following transfection, the cell morphology was observed using a phase-contrast microscope.…”

“…Accordantly, our previous study has also reported that compounds increase insulin signaling can enhance protein clearance and therefore reduce the mHtt-induced neurotoxicity in neuronal cells. It seems that the restoration of insulin sensitivity attenuates mHtt-induced oxidative stress and increases autophagy, thereby enhancing the viability of neuronal cells [8]. However, how mHtt interferes with insulin signaling in neurons is still to be determined.…”

Recent progress in the role of autophagy in neurological diseases

“…Moreover, acetylation at Lys444 of mHTT [200] and upregulation of HSC70 and lamp2A [201] have been regarded as the novel therapies to remove mHTT by autophagy. Additionally, some drugs may also be useful for the treatment of HD, such as rilmenidine [202], histone deacetylase (HDAC) inhibitors [203], CTEP (a negative allosteric modulator of metabotropic glutamate receptor 5 (mGluR5)) [204], liraglutide (a GLP-1 analogue) [205], neferine (a bisbenzylisoquinoline alkaloid isolated from the lotus seed embryo of Nelumbo nucifera Gaertn) [206], their targets are listed in Table 1 .…”