Grant: Operating Grant - Priority Announcement: ALS Canada Research Fund

Amyotrophic lateral sclerosis (ALS) is a devastating disease that attacks nerve cells that control muscles, resulting in progressive paralysis and eventual death. The disease afflicts ~30,000 individuals in North America, with 5,000 new cases per year. It has been clinically observed that ALS spreads systematically from one region to another, starting from the area of onset, and does not skip anatomical regions. One way to explain this observation is the cell-to-cell spread of disease-causing factors through the nervous system; however, no such disease mechanism for this has yet to be confirmed. The misfolded protein SOD1 has been implicated in ALS disease biology and has been shown to trigger the spread of misfolding to other SOD1 molecules. Our laboratory has discovered the molecular basis of this propagated SOD1 misfolding, which we have shown is capable of being transmitted from cell to cell. Mutation in SOD1 is one way in which the protein is induced to misfold and aggregate; however SOD1 mutations are only found in ~2% of total ALS cases. ALS patients without SOD1 mutations show evidence of misfolded SOD1 and other traits common to ALS cases with SOD1 mutations, such as decreased levels of proteasome markers, the machinery responsible for regulating misfolded protein inside the cell. We propose that misfolded WTSOD1 is a common molecular determinant in the progression and disese biology of ALS, contributing to nerve cell death directly through increased production of toxic factors, as well as indirectly by overwhelming the protein regulation machinery. Our study not only hopes to define the role of misfolded WTSOD1, but to identify other targets that contribute to its generation. Confirmation of misfolded WTSOD1 as a single potent target for all cases of ALS will allow for the rational design of a common ALS therapeutic.