Compromised IGF signaling causes caspase-6 activation in Huntington disease
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Compromised IGF signaling causes caspase-6 activation in Huntington disease. / Skotte, Niels Henning; Pouladi, Mahmoud A.; Ehrnhoefer, Dagmar E.; Huynh, Katie; Qiu, Xiaofan; Nielsen, Signe Marie Borch; Nielsen, Troels Tolstrup; Nørremølle, Anne; Hayden, Michael R.
In: Experimental Neurology, Vol. 332, 113396, 2020.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Compromised IGF signaling causes caspase-6 activation in Huntington disease
AU - Skotte, Niels Henning
AU - Pouladi, Mahmoud A.
AU - Ehrnhoefer, Dagmar E.
AU - Huynh, Katie
AU - Qiu, Xiaofan
AU - Nielsen, Signe Marie Borch
AU - Nielsen, Troels Tolstrup
AU - Nørremølle, Anne
AU - Hayden, Michael R.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - Caspase-6
KW - Huntingtin
KW - Huntington disease
KW - Insulin-like growth factor binding proteins, and neuroprotection
KW - Insulin-like growth factor-1
KW - Proteolysis
U2 - 10.1016/j.expneurol.2020.113396
DO - 10.1016/j.expneurol.2020.113396
M3 - Journal article
C2 - 32622701
AN - SCOPUS:85087775983
VL - 332
JO - Experimental Neurology
JF - Experimental Neurology
SN - 0014-4886
M1 - 113396
ER -
ID: 244916384