Grant: Foundation Grant

The brain is the most fragile organ both physically and biochemically. Brain cells do not regenerate so they have to last a lifetime in face of wide range of stresses: physical, chemical, and biological. To deal with these, neurons have evolved protective mechanisms. The goal of our research is to understand these defences and develop new therapies to treat or prevent the progression of neurodegenerative diseases, which are an increasingly serious public health problem. We are focusing on Parkinson's disease, which afflicts some 60,000 Canadians, and a genetic disease, ARSACS, first identified in Quebec. Both diseases involve perturbations in the ubiquitin-proteasome system, part of the cellular recycling machinery that is used to identify and remove damaged proteins and organelles. The approach we are using is to visualize protein complexes in the ubiquitin-proteasome system using the tools of structural biology. Seeing how the proteins work will allow us to design therapies. Parkinson's disease can be caused by mutations in a quality control system for mitochondria. In healthy neurons, a protein kinase PINK1 detects damaged mitochondria and then signals Parkin, a component in the ubiquitin-proteasome system, to start the degradation process. Defects in either step cause a genetic, early onset form of Parkinson's disease. The second disease, ARSACS, is caused by loss of Sacsin, a protein chaperone that helps mitochondria split apart (mitochondrial fission). Through mechanisms not yet understood, this leads to a slow progressive loss of Purkinje cells, which control movement. Understanding and developing treatments for these diseases will also help in the treatment of other dementias. There is evidence for impaired mitochondrial function in Alzheimer's, Huntington's disease, and amyotrophic lateral sclerosis. The proposed studies of the ubiquitin-proteasome system will set the stage for the development of new drugs for neurodegenerative diseases.