Huntingtin proteolysis in Huntington disease

The hypothesis that hit proteolysis represents a critical step in Huntington disease (HD) pathogenesis was first suggested in 1996 when hit was identified as a substrate for caspase-3. Indeed, hit was the first caspase substrate to be identified in the brain. Since that time, the identification of caspase-generated N-terminal hit fragments in the patient brain and the accelerated phenotype of transgenic mice expressing truncated fragments of htt support the hypothesis that htt proteolysis contributes to the pathogenesis of htt. However, selective and quantitative neuronal loss has so far been observed only in mice with expression of full-length human htt, suggesting the possibility that generating htt fragments from the intact protein may be essential for selective neuronal loss to be evident. Furthermore, a characteristic neuropathological hallmark of HID in patient brain and animal models is the presence of intracellular aggregates composed of htt fragments containing the polyglutamine expansion. Because numerous Studies have demonstrated enhanced cytotoxicity and aggregenic potential of amino-terminal hit fragments containing expanded polyglutamine repeats, an understanding of precisely how hit is cleaved within the brain may result in novel therapeutic approaches for HD. In this review, we integrate many observations on proteolysis in HID, attempt to synthesize a coherent view of how proteolysis may contribute to the pathogenesis of HD, and comment on the future potential of protease inhibitors as a therapeutic strategy for this devastating illness. (C) 2003 Elsevier B.V. All rights reserved.