Abstract
BackgroundHuntington Disease (HD) is a neurodegenerative disorder in which caspase activation and cleavage of substrates, including the huntingtin protein, has been invoked as a pathological mechanism. Specific changes in caspase-2 (casp2) activity have been suggested to contribute to the pathogenesis of HD, however unique casp2 cleavage substrates have remained elusive. We thus utilized mice completely lacking casp2 (casp2-/-) to examine the role played by casp2 in the progression of HD. This 'substrate agnostic' approach allows us to query the effect of casp2 on HD progression without pre-defining proteolytic substrates of interest.ResultsYAC128 HD model mice lacking casp2 show protection from well-validated motor and cognitive features of HD, including performance on rotarod, swimming T-maze, pre-pulse inhibition, spontaneous alternation and locomotor tasks. However, the specific pathological features of the YAC128 mice including striatal volume loss and testicular degeneration are unaltered in mice lacking casp2. The application of high-resolution magnetic resonance imaging (MRI) techniques validates specific neuropathology in the YAC128 mice that is not altered by ablation of casp2.ConclusionsThe rescue of behavioral phenotypes in the absence of pathological improvement suggests that different pathways may be operative in the dysfunction of neural circuitry in HD leading to behavioral changes compared to the processes leading to cell death and volume loss. Inhibition of caspase-2 activity may be associated with symptomatic improvement in HD.
Highlights
Huntington Disease (HD) is a neurodegenerative disorder in which caspase activation and cleavage of substrates, including the huntingtin protein, has been invoked as a pathological mechanism
Huntington disease (HD) is a neurodegenerative disorder characterized by progressive motor, cognitive and psychiatric deficits [1] caused by an expanded poly-glutamine tract in the huntingtin (HTT) protein [2]
Consistent with this human data, quantitative realtime PCR (QRT-PCR) of striatal casp2 mRNA demonstrates that wild type (WT) and YAC128 mice have equivalent levels throughout their life spans (table 1, two-way ANOVA, Genotype: F(1,27) = 0.073, p = 0.79; Age: F(3,27) = 2.48, p = 0.082; Interaction: F(3,27) = 2.71, p = 0.065)
Summary
Huntington Disease (HD) is a neurodegenerative disorder in which caspase activation and cleavage of substrates, including the huntingtin protein, has been invoked as a pathological mechanism. We utilized mice completely lacking casp (casp2-/-) to examine the role played by casp in the progression of HD. The commonality of caspase cleavage of neurodegenerative disease proteins could reflect their degradative clearance during cell death. These cleavage events could mediate apoptotic signaling, as is the case for bid [15], XIAP [16] and the caspases themselves [17]. Prevention of caspase processing of both atrophin-1 [23] and ataxin-7 [14] reduces toxicity in vitro These experiments suggest that caspasemediated cleavage of neurodegenerative disease proteins plays a role in the development of these conditions
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