Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

Huntington disease (HD) is an adult-onset, neurological disease that affects muscle coordination and eventually results in cognitive decline and dementia. There are presently no effective treatments or cures and death occurs approximately 15-20 years after disease onset. HD is caused by an inherited mutation in the huntingtin gene, leading to the production of an altered version of the huntingtin protein that accumulates as aggregates. These aggregates can be cleared from the cell through autophagy, a mechanism that degrades unwanted proteins. During the development of this disorder, we know that autophagy becomes defective over time. We also know that certain proteases (proteins which cut other proteins) including caspase-6 (C6) have increased activity and it has been shown that these proteases in fact cleave key proteins involved in carrying out autophagy. The hypothesis is that cleavage of autophagy proteins by C6 leads to their loss of function and subsequent impairment of the autophagy process. This then results in reduced clearance of aggregates and further progression of the disease. I will determine what the functional impact is on autophagy-mediated clearance of protein aggregates following cleavage of autophagy proteins by C6. I will then reduce the activity of these proteases and render these autophagy proteins resistant to cleavage in order to increase autophagy and promote aggregate clearance. Thus, the goal of this project is to investigate the relationship between altered protease activity and impaired autophagy, and how this contributes to the pathogenesis in Huntington disease. We can then use this information to develop specific therapies aimed at inhibiting C6 and promoting the clearance of aggregates, ultimately resulting in the amelioration of HD symptoms. This research is significant as it will reveal important mechanisms involved in the progression of Huntington disease and will lead to the development of new therapeutic approaches.