Apoptosis block halts Huntington's disease

New studies in mice indicate that inhibition of an enzyme involved in apoptosis might be a useful therapeutic strategy for Huntington's disease (HD).

Apoptosis is thought to be involved in the pathogenesis of HD, but how mutant huntingtin protein leads to cell death is unknown. Activation of caspase-1--a protease involved in triggering apoptosis--"seems to be a shared common pathway of many neurological diseases", explains Robert Friedlander (Brigham and Women's Hospital, Boston, MA, USA), and "previous publications have shown that caspase-1 can cleave huntingtin".

To find out how caspase-1 might be involved in HD, Friedlander's team crossbred mice expressing mutant human huntingtin with mice with no caspase-1 activity. Onset of symptoms was delayed and survival extended in the doubly mutant mice, compared with mice with the huntingtin mutation only. This phenotypic change was associated with loss of cleavage of mutant huntingtin. Finally, administration of a caspase inhibitor into the cerebral ventricles of the HD-type mice slowed disease and delayed mortality (Nature 1999; 399: 263-67 ). Friedlander speculates that mutant huntingtin somehow causes a toxic state within the cell, which activates caspase-1. The protease then seems to "cleave mutant huntingtin, generating toxic huntingtin fragments" and setting up "a feedback loop that eventually leads to cell dysfunction and death".

Christian Haass (University of Munich, Germany) believes that the team has provided "double proof that apoptosis plays a major role in the pathology of the disease" and that "if you block caspase, you block [HD]". The next step, says Haass, is clinical trials of caspase inhibitors. "The good thing about caspases is that they . . . can be inhibited very specifically without affecting any other proteases. [But] these drugs have to cross the blood-brain barrier and that's very difficult to achieve." Friedlander adds that the inhibitor used in his study is not suitable for use in people but that he is keen to do clinical trials once suitable caspase inhibitors have been developed.

Kelly Morris