期刊
JOURNAL OF NEUROSCIENCE
卷 25, 期 50, 页码 11645-11654出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4181-05.2005
关键词
Cop; Rip2; caspase-1; Huntington's disease; RNA interference; cell death
资金
- NIGMS NIH HHS [GM61694] Funding Source: Medline
- NINDS NIH HHS [R01 NS041635, NS41635, NS39324, R01 NS039324] Funding Source: Medline
Caspase-1 plays a role in the pathogenesis of a variety of neurological diseases. Caspase-1 activation is an early event in models of Huntington's disease (HD). However, mechanisms regulating the activation of this apical caspase in cell death are not known. Receptor interacting protein-2 (Rip2) and caspase recruitment domain (CARD) only protein (Cop) are two CARD proteins with significant homology to the caspase-1 CARD and modulate caspase-1 activation in inflammation. Rip2 is a caspase-1 activator, and Cop is a caspase-1 inhibitor. We demonstrate in models of HD that caspase-1 activation results from dysregulation of caspase-1 activation pathways. Associated with disease progression, we detect elevation of the caspase-1 activator Rip2 and reduction of the caspase-1 inhibitor Cop. Knocking down endogenous Rip2/Cop respectively results in reduced/increased sensitivity to neurotoxic stimuli. Our data provide evidence that caspase-1-mediated cell death is regulated, at least in part, by the balance of Rip2 and Cop, and alterations of this balance may contribute to aberrant caspase-1-mediated pathogenesis in Huntington's disease.
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