Correlating quaternary structure of pathological protein aggregates with phenotypic presentation of ALS
Aperçu du projet
Amyotrophic lateral sclerosis (ALS) is a disease of progressive weakness that leads to death within a few years of onset. The disease can start in one arm, leg, or face, but it inevitably spreads to all areas, killing cells as it spreads. What if, once the disease starts, we could stop it from spreading or killing cells? We would save lives. To do this, we must first understand what drives the spreading and the cell death. In almost all cases of ALS, there is a buildup of misfolded protein that can cause its neighbour proteins to misfold, leading to spreading misfolding throughout the nervous system. This spreading is called “prion-like” because it mimics what happens in prion disease (eg. mad cow disease). In prion disease, the prion protein misfolds into different shapes and clumps together into different sizes; these shapes and sizes influence the prions ability to spread and its toxicity. We propose that the size and shape of misfolded proteins is also important in ALS. In ALS there are multiple proteins that can misfold, spread and become toxic, and these proteins can influence one another. How do we identify which protein sizes and shapes are most important? We need a method to isolate all misfolded protein particles from patients, test each particle’s spreading and toxic properties, and measure different protein particle interactions. My lab does exactly this from prion-infected brain samples and we propose to apply the same method to ALS. We have eight ALS patient brains and we will separate out all the protein particles from different brain regions and measure their spreading efficiency and toxicity. By identifying the most efficient or neurotoxic ALS particle(s), we may learn why some patients progress faster than others and we will know which particle to target for treatment.
Chef d'équipe
Valerie Sim , University of Alberta
Partenaire et Donateurs
ALS Society of Canada