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• W3038511595 endingPage "113396" @default.
• W3038511595 startingPage "113396" @default.
• W3038511595 abstract "Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expansion of a polyglutamine repeat in the huntingtin (HTT) protein. Aberrant activation of caspase-6 and cleavage of mutant HTT generating the toxic N-terminal 586 HTT fragment are important steps in the pathogenesis of HD. Similarly, alterations in the insulin-like growth factor 1 (IGF-1) signaling pathway have been implicated in the disease as a result of decreased plasma IGF-1 levels in HD patients. In addition, two recent studies have demonstrated therapeutic benefit of IGF-1 treatment in mouse models of HD. Since IGF-1 promotes pro-survival pathways, we examined the relationship between IGF-1 signaling and aberrant caspase-6 activation in HD. Using immortalized mouse striatal cells expressing wild-type (STHdhQ7) or mutant HTT (STHdhQ111), we show that reduced levels of IGF-1 are associated with enhanced activation of caspase-6, increased cell death, and mutant HTT cleavage in a cellular stress paradigm. We demonstrate that IGF-1 supplementation reverses these effects and lowers the level of the toxic 586 HTT fragment. In addition, transcriptional analysis in the R6/2 HD transgenic mouse model demonstrated that the IGF-1 signaling system is dysregulated at multiple levels in several tissues including liver, muscle, and brain. Among these changes, we found increased expression of IGF-1 binding protein 3 (IGFBP-3), which may further reduce the bioavailability of IGF-1 as a consequence of increased IGF-1 binding. Our findings thus suggest that the therapeutic benefit of IGF-1 supplementation in HD may be significantly improved if other defects in the IGF-1 signaling pathway are corrected concurrently." @default.
• W3038511595 created "2020-07-10" @default.
• W3038511595 creator A5006854193 @default.
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• W3038511595 date "2020-10-01" @default.
• W3038511595 modified "2023-09-29" @default.
• W3038511595 title "Compromised IGF signaling causes caspase-6 activation in Huntington disease" @default.
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• W3038511595 doi "https://doi.org/10.1016/j.expneurol.2020.113396" @default.

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