Inhibition of caspase-6: A potential therapy for Huntington’s disease

Huntington’s disease (HD) is an inherited, neurodegenerative disorder that affects one in every ten thousand North Americans and for which there is currently no cure. HD is caused by an increase in the length of a CAG tri-nucleotide repeat array within the HD gene, leading to expansion of a polyglutamine tract within the huntingtin protein (htt). The mutant huntingtin protein (mhtt) is known to cause selective degeneration of neurons in the striatum resulting in movement and cognitive dysfunction. The molecular basis of mhtt-dependent HD pathology is unclear, but a recent study has shown that inhibiting cleavage of mhtt by the protease caspase-6 is sufficient to halt death of striatal neurons and behavioral dysfunction in a rodent model of HD. In this report, current hypotheses concerning the molecular basis of HD, and existing and experimental therapies for treating HD will be reviewed with particular emphasis on the potential development of anti-caspase-6 drugs that may provide the most promising breakthrough yet for treating this devastating disorder.