Mutant huntingtin aggregates do not sensitize cells to apoptotic stressors

It has been postulated that neuronal inclusions composed of mutant huntingtin may play a causative role in the pathogenesis of Huntington's disease. To study the putative role of aggregates in modulating apoptotic vulnerability, SH-SY5Y cell lines stably expressing truncated huntingtin with 18 (wildtype) (N63-18Q) or 82 (mutant) (N63-82Q) glutamine repeats were established. Aggregates were observed in similar to 13% of the N63-82Q cells; no aggregates were observed in the N63-18Q cells. In response to apoptotic stimuli such as staurosporine or hyperosmotic stress, caspase-3 activity was significantly greater in the N63-82Q cells compared to the N63-18Q cells. However, double immunostaining for huntingtin and active caspase-3 revealed that the presence of aggregates did not correlate with the presence of active caspase-3, indicating that aggregates do not contribute to the increase in apoptosis in the N63-82Q cells. (C) 2002 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.