Grant: Project Grant

The brain is the most fragile organ both physically and biochemically. Neurons must last a lifetime in the face of physical, chemical, and biological stresses since they do not regenerate. To deal with this challenge, brain cells have evolved protective mechanisms. The goal of our research is to use structural biology to understand these defenses and develop new therapies to treat and prevent the progression of neurodegenerative diseases - an increasingly serious public health burden. We are working on Parkinson's disease, a motor system disorder, which afflicts some 70,000 Canadians. At a biochemical level, Parkinson disease arises from perturbations in the ubiquitin-proteasome system, the cellular machinery that identifies and removes damaged proteins and organelles. The approach we are using is to visualize protein complexes in the ubiquitin-proteasome system with the tools of structural biology. Revealing the shape of proteins allows us to understand how they function and design small molecules to control them. Our research in Parkinson's disease will shed light on how we treat other dementias. There is evidence for dysfunction of the ubiquitin-proteasome system in Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. The proposed studies will set the stage for the development of disease-modifying treatments for these neurodegenerative diseases.