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The Journal of Neuroscience, December 14, 2005, 25(50):11645-11654; doi:10.1523/JNEUROSCI.4181-05.2005

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Neurobiology of Disease
Dysregulation of Receptor Interacting Protein-2 and Caspase Recruitment Domain Only Protein Mediates Aberrant Caspase-1 Activation in Huntington's Disease

Xin Wang,1 Hongyan Wang,1 Bryan E. Figueroa,1 Wen-hua Zhang,1 Chunfeng Huo,1 Yingjun Guan,1 Yu Zhang,1 Jean-Marie Bruey,2 John C. Reed,2 and Robert M. Friedlander1

1Neuroapoptosis Laboratory, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, and 2Burnham Institute for Medical Research, La Jolla, California 92037

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.

Key words: Cop; Rip2; caspase-1; Huntington's disease; RNA interference; cell death

Received June 27, 2005; accepted October 27, 2005.






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