Recent evidence implicates caspase-mediated cell death pathways in several neurological disorders. In particular, inappropriate activation of caspase-1 and -3 leads to the death of cortical and striatal neurons in Huntington's disease (HD). We contend that understanding the roles of these """"""""Cysteine-dependent, ASPartate-directed proteASES"""""""" in HD will suggest therapies for this untreatable and universally fatal syndrome. The following four lines of investigation examine the molecular pathology of HD and ways to restore healthy physiology via genetic and pharmacological therapies. 1) Normal huntingtin protein (htt) as an antagonist to cell death: Htt is both a substrate for and an inhibitor of caspase-3. Therefore, we hypothesize that depletion of huntingtin is both a consequence of HD and a cause of progressive ailment. Expression of excess htt in cultured cells should break this detrimental feedback loop. In addition to that in vitro test of the """"""""runaway caspase"""""""" hypothesis, whole animal experiments will be conducted. A transgenic mouse will be constructed to have elevated systemic levels of htt. The animal will be tested for its predicted resistance to HD. 2 and 3) While the first line of research concerns the effects of a caspase pathway, these two sets of experiments investigate signals that initiate one. As discussed within the application, activation of caspase-1 is among the earliest molecular changes associated with HD. Experiments are proposed to investigate the proteins that modulate caspase-1: the activator Rip2 and the inhibitor Cop. CARD-mediated interactions among caspase-1 and these antagonistic regulators determine the level of enzyme activity. Furthermore, expression of both Rip2 and Cop is aberrant in the brains of R6/2 mice (animal models of HD) and in post mortem samples from human HD patients. We propose genetic manipulations of cells and of mice with the aim of restoring proper caspase-1 homeostasis, and inhibiting disease progression. 4) Minocycline has been demonstrated to slow disease progression in HD mice. The combined effect of minocycline with creatine and coenzyme Q (two Compounds that other researchers find to slow disease progression in HD mice) shall be evaluated. These compounds have different modes of action, suggesting that their salutary effects will reinforce one-another. Combination therapies will be tested using HD mice.
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