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

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...

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Autores principales: Chang, Ching-Chi, Lin, Tzu-Chin, Ho, Hsiao-Li, Kuo, Chien-Yin, Li, Hsin-Hua, Korolenko, Tatiana A., Chen, Wei-Jen, Lai, Te-Jen, Ho, Ying-Jui, Lin, Chih-Li
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6164932/
https://www.ncbi.nlm.nih.gov/pubmed/30149534
http://dx.doi.org/10.3390/ijms19092505
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author Chang, Ching-Chi
Lin, Tzu-Chin
Ho, Hsiao-Li
Kuo, Chien-Yin
Li, Hsin-Hua
Korolenko, Tatiana A.
Chen, Wei-Jen
Lai, Te-Jen
Ho, Ying-Jui
Lin, Chih-Li
author_facet Chang, Ching-Chi
Lin, Tzu-Chin
Ho, Hsiao-Li
Kuo, Chien-Yin
Li, Hsin-Hua
Korolenko, Tatiana A.
Chen, Wei-Jen
Lai, Te-Jen
Ho, Ying-Jui
Lin, Chih-Li
author_sort Chang, Ching-Chi
collection PubMed
description 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.
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spelling pubmed-61649322018-10-10 GLP-1 Analogue Liraglutide Attenuates Mutant Huntingtin-Induced Neurotoxicity by Restoration of Neuronal Insulin Signaling Chang, Ching-Chi Lin, Tzu-Chin Ho, Hsiao-Li Kuo, Chien-Yin Li, Hsin-Hua Korolenko, Tatiana A. Chen, Wei-Jen Lai, Te-Jen Ho, Ying-Jui Lin, Chih-Li Int J Mol Sci Article 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. MDPI 2018-08-24 /pmc/articles/PMC6164932/ /pubmed/30149534 http://dx.doi.org/10.3390/ijms19092505 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Chang, Ching-Chi
Lin, Tzu-Chin
Ho, Hsiao-Li
Kuo, Chien-Yin
Li, Hsin-Hua
Korolenko, Tatiana A.
Chen, Wei-Jen
Lai, Te-Jen
Ho, Ying-Jui
Lin, Chih-Li
GLP-1 Analogue Liraglutide Attenuates Mutant Huntingtin-Induced Neurotoxicity by Restoration of Neuronal Insulin Signaling
title GLP-1 Analogue Liraglutide Attenuates Mutant Huntingtin-Induced Neurotoxicity by Restoration of Neuronal Insulin Signaling
title_full GLP-1 Analogue Liraglutide Attenuates Mutant Huntingtin-Induced Neurotoxicity by Restoration of Neuronal Insulin Signaling
title_fullStr GLP-1 Analogue Liraglutide Attenuates Mutant Huntingtin-Induced Neurotoxicity by Restoration of Neuronal Insulin Signaling
title_full_unstemmed GLP-1 Analogue Liraglutide Attenuates Mutant Huntingtin-Induced Neurotoxicity by Restoration of Neuronal Insulin Signaling
title_short GLP-1 Analogue Liraglutide Attenuates Mutant Huntingtin-Induced Neurotoxicity by Restoration of Neuronal Insulin Signaling
title_sort glp-1 analogue liraglutide attenuates mutant huntingtin-induced neurotoxicity by restoration of neuronal insulin signaling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6164932/
https://www.ncbi.nlm.nih.gov/pubmed/30149534
http://dx.doi.org/10.3390/ijms19092505
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