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Impact of caspase-6 modulation on Huntington disease phenotypes in the YAC128 mouse model Ladha, Safia

Abstract

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms. HD is caused by a CAG repeat expansion in the huntingtin (HTT) gene leading to the production of the mutant huntingtin protein (mHTT). Caspase-6 (C6) is a cysteine aspartyl protease that plays a central role in apoptosis and has been postulated to play a role in inflammation. Increased C6 activation is observed in human HD brains and mouse models and the inhibition of C6-mediated cleavage of mHTT protects against neuropathology and behavioural deficits in the YAC128 mouse model of HD. Additionally, alterations in inflammation are a feature of many neurodegenerative diseases, including HD. Hyperactive inflammatory responses are observed in both HD patients and mouse models and C6 has been postulated to play a role in mediating inflammation. Constitutive deletion of the Casp6 gene (denoted as C6) in YAC128 mice results in a partial rescue of some features of HD; however, the continued presence of the 586 cleavage fragment in the absence of C6 suggests possible compensation by other proteases. The goal of this thesis was to investigate the impact of modulating C6 in the adult YAC128 mouse and to further characterize the role of C6 in inflammation. To that end, the C6 gene was partially deleted in the adult YAC128 mouse and characterization of these mice reveals no amelioration in motor or cognitive phenotypes but a modest improvement in certain psychiatric behaviours. Neuropathological assessment shows no attenuation in canonical brain pathology but peripherally, the loss of C6 attenuates the overactive inflammatory response observed in YAC128 mice. These data suggest that partial loss of C6 in the brain is not sufficient to improve most behavioural and neuropathological phenotypes but implicate C6 in the regulation of inflammation. Furthermore, loss of C6 results in a blunted inflammatory response characterized by reduced cytokine release. As the presence of elevated cytokine levels have been suspected to cause psychiatric behaviours such as depression, this finding provides a possible mechanistic link between C6 activity and the onset of affective behaviours.

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Attribution-NonCommercial-NoDerivatives 4.0 International

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