HD is caused by a trinucleotide repeat (CAG) encoding glutamine near the N-terminus of the protein huntingtin (htt).  The number of CAG repeats corresponds with the risk and age of onset of the disease. Normal range is about 28 while greater than 60 results in juvenile onset HD. Htt is a 348 kDa multidomain protein, which is widely expressed, but whose functions are poorly understood.  In both human and mouse model HD, mutant N-terminal fragments of htt (N-mhtt) accumulate in the cytoplasm and nucleus forming inclusions.  The presence of mutant N-terminal fragments results in neural degradation primarily located at the basal ganglia.

For years, research has focused on determining if a specific protease could be the rate-determining step in the release of the toxic N-mhtt, as it would be an attractive drug target for direct treatment of the disease.  Several proteases have been considered as targets for HD including caspases, calpains and aspartyl endopeptidases. All of these proteins have been shown to cleave mhtt into N-terminal fragments that accumulate in the nucleus of cells resulting in inclusions, and there was no single enzyme that stood out among the others.  Recently a study using YAC mice expressing caspase-3 and caspase-6 resistant mhtt have shown that mice expressing caspase-6 but not caspase-3 resistant mhtt have a dramatically ameliorated neurodegenerative phenotype compared to mice expressing similar levels of unchanged full-length mutant Htt.  The caspase-6 resistant mice were protected from neuronal degradation, had a significant delay in accumulation of N-mhtt fragments in the nucleus, and had a dramatic decrease of the behavioral phenotype related to HD.  Furthermore, caspase-6 resistant mice were protected from excitotoxic cell death, as initiated by N-methyl-D-aspartic acid, quinolinic acid and staurosporine.  These data are highly suggestive that cleavage at the caspase-6 site in mhtt is a crucial rate-limiting step in the pathogenesis of HD.  Hence, blocking the cleavage by inhibition of caspase-6 is an exciting new approach for the direct treatment of HD patients.