Grant: Doctoral: Vanier Canada Graduate Scholarships

Protein misfolding is the process by which a previously useful protein may adopt a new configuration that impairs its function and harms nearby cells. Misfolded prion protein is the causative agent for Creutzfeldt-Jakob disease in humans and mad cow disease in cattle, while misfolded superoxide dismutase 1 is involved in familial amyotrophic lateral sclerosis (ALS). The implications of these diseases for human suffering are vast: there are no curative therapies, so only palliative care is possible. As well, misfolding diseases impose a large economic burden: a single case of mad cow disease in 2003 caused a food safety crisis that cost Canadian farmers over $5 billion. Thermodynamics and statistical physics provide tools to understand protein misfolding and design drugs that can interfere with it. It is most likely that unstable parts of proteins are the first to be involved in misfolding, so antibodies that can recognize changes in the organization of these regions can block the early events that predispose to later misfolding and thereby reduce further accumulation of pathologic protein. A computational method is in development that predicts suitable antibody binding sites by calculating several thermodynamic variables that affect stability for all subsequences of a protein. Rabbits will be immunized with short protein segments that have the same sequence as the unfolding-prone regions. Using a new screening technology, a large number of antibody-producing cells will be probed to identify those generating the highest affinity antibodies, and they will be tested for their binding strength to the folded and misfolded protein. Antibodies that successfully pass these tests will be used in mouse models of prion disease and ALS to demonstrate a survival advantage. This project offer the exciting prospect of improved treatment of two currently fatal conditions, with large health benefits accruing to Canadians affected by these diseases if successful.