p53 increases caspase-6 expression and activation in muscle tissue expressing mutant huntingtin

Abstract

Activation of caspase-6 in the striatumof both presymptomatic and affected persons with Huntington's disease (HD) is an early event in the disease pathogenesis. However, little is known about the role of caspase-6 outside the centralnervous system(CNS)andwhether caspaseactivation might play a role in the peripheralphenotypes, such as muscle wasting observed in HD.We assessed skeletal muscle tissue from HD patients and well-characterized mouse models of HD. Cleavage of the caspase-6 specific substrate lamin A is significantly increased in skeletal muscle obtained from HD patients as well as in muscle tissues from two different HD mouse models. p53, a transcriptional activator of caspase-6, is upregulated in neuronal cells and tissues expressing mutant huntingtin. Activation of p53leads to a dramatic increase in levels of caspase-6mRNA,caspase-6 activity and cleavage of lamin A. Using mouse embryonic fibroblasts (MEFs) from YAC128 mice, we show that this increase in caspase-6 activity can be mitigated by pifithrin-α (pifα), an inhibitor of p53 transcriptional activity, but not through the inhibition of p53's mitochondrial pro-apoptotic function. Remarkably, the p53-mediated increase in caspase-6 expression and activation is exacerbated in cells and tissues of both neuronal and peripheral origin expressing mutant huntingtin(Htt).These findings suggest that the presence of the mutant Htt protein enhances p53 activity and lowers theapoptotic threshold,whichactivates caspase-6.Furthermore, these results suggest that this pathway is activated both within and outside the CNS in HD and may contribute to both loss of CNS neurons and muscle atrophy. © The Author 2013. Published by Oxford University Press. All rights reserved.