The role of the proteasome in Huntington’s disease

Huntington’s disease is a heritable neurodegenerative disease with a slow but fatal progression. Affected patients suffer from involuntary movements, changes in behavior and cognitive impairment. The disease is initiated by an expansion of the polyglutamine (polyQ) sequence in the huntingtin protein. Due to this expansion, the protein becomes misfolded and forms intracellular aggregates that are mainly present in the nucleus. The ubiquitin proteasome system is the major degradation system that is present in both the cytoplasm and nucleus of cells. It has been suggested that the ubiquitin proteasome system does not function properly in Huntington’s disease and cannot efficiently clear misfolded huntingtin proteins. In this thesis we explore role of the proteasome in Huntington’s disease. We showed that polyQ peptides that may be generated by the proteasome are peptidase resistant an aggregation prone and we studied the effects of chaperones on these polyQ peptides. Furthermore, we show that proteasomes are able to completely degrade the mutant huntingtin protein and that proteasomes do not become impaired in polyQ aggregates. This raised the question whether we could modulate the proteasome to even improve mutant huntingtin degradation in cells. Finally, we show that changing protesomal activity improves mutant huntingtin degradation. Together these findings contribute to a better understanding of mutant huntingtin processing by proteasomes.