Grant: CIHR Fellowship

Huntington disease is an inherited degenerative brain disorder that affects 1 in 7,500 individuals in the Western world. It is characterised by involuntary movements, cognitive deficits, and dementia leading ultimately to death. The cause of Huntington disease is a mutation in the HTT gene, which then produces the toxic mutant huntingtin protein. This mutant protein disrupts many vital cellular functions, and is ultimately responsible for the brain cell death. There is no cure for this disorder. Targeting the cause of Huntington disease by reducing mutant huntingtin in the brain should prevent or delay disease onset. One approach to reducing mutant huntingtin is to promote its degradation in cells. I will target mechanisms that should increase clearance of mutant huntingtin from the cells, and reduce its toxicity. The huntingtin protein is normally subjected to a variety of modifications (addition of small molecules) that allow it to be functional and properly degraded in cells. However, these modifications are altered in the mutant protein, which decreases the brain's ability to eliminate the toxic protein. Our lab has previously identified specific modifications of huntingtin that play key roles in Huntington disease when altered: restoring their levels in transgenic mice can improve, and even suppress, Huntington disease symptoms. My research now suggests that key modifications of huntingtin regulate each other and regulate the elimination of the protein through autophagy, a degradation process abnormally reduced in Huntington disease. The objectives of my project are to investigate modifications of huntingtin in vitro and in vivo in Huntington disease mouse models to characterise the interrelationships between these modifications, and evaluate how they regulate mutant huntingtin degradation. My ultimate goal is to identify relevant modifications to target in order to elaborate therapeutic strategies to enhance mutant huntingtin degradation through autophagy.