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sector_ico_Health_trans Human Health

Propagated protein misfolding of SOD1 in ALS: Exemplar for Neurodegeneration

  • Project Leaders: Neil Cashman
  • Institutions: University of British Columbia (UBC)
  • Budget: $1500000
  • Program/Competition: Partner Programs
  • Genome Centre(s): Genome British Columbia
  • Fiscal Year: 2013
  • Status: Closed

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a progressive fatal disease that affects the nerve cells responsible for muscle movement. 30,000 individuals in North America are currently suffering from the disease; 2-3 Canadians are lost to ALS every day.

The project ultimate goal was to improve the treatment options for ALS patients. To achieve this goal, the team proposed a comprehensive research program that should enhance our understanding of the SOD1 protein conversion process, producing toxic misfolded species. Hopefully, this will have broad application to all neurodegenerative diseases in which abnormal protein conversion is implicated. During this project the group established the importance of tryptophan at position 32 of the SOD1 protein for the propagated misfolding and aggregation of SOD1, demonstrated that over-production of misfolded SOD1 in transgenic mice directly contributed to progressive motor neuron loss, and showed that small molecules can block this misfolding and spread of pathology, in a dose-dependent manner. The group also developed a high-throughput assay for an effective screening of small molecules that inhibit SOD1 misfolding, with the goal of identifying more compounds that might be used in human ALS therapeutic trials