Grant: Project Grant

Huntington's disease (HD) is one of nine neurological diseases caused by DNA expansion in genes. This disease affects 1 in 7000 Canadians, is progressive and fatal, and has no direct treatment. The result of this DNA expansion is a long tract of glutamine amino acids that alter the function of the protein, leading to disease. However, while people are born with these expansions, disease does not occur until later in life, and the presence of the mutation only explains half of when, and how severe their disease will be. Based on HD patient DNA, we now know that DNA repair genes make up most of the pathways that affect the age of disease start and severity, and that these genes are important for other CAG diseases. The Truant lab was the first group worldwide to show that huntingtin protein is a DNA damage repair protein, and that the switch to turn it on is a type of stress that increases as all humans age. We have discovered a new type of pathway that appears to be able to fix the mutant huntingtin protein and restore this DNA repair. This data allowed us to formulate a fundamental new idea of how this diseases are triggered, which has important implications for more common degenerative brain diseases for which half the Canadian population is at risk over age 65. The excitement from this work is that we have a new drug lead, with industry development, aset of pathways well understood by cancer research and a potential list of drugs that may be effective in these diseases. We are using an approach referred to as Chemical Biology, in which we use compounds and drugs to affect our study systems in cells taken directly from HD patients.This research is done in the context of state-of-the art microscopy methods ondevices we have developed and use at McMaster University