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Propagated protein misfolding of SOD1 in ALS: Exemplar for neurodegeneration

Principal Investigator:
  • Neil Cashman, University of British Columbia
Team Members:
  • Jean-Pierre Julien, Université Laval
  • Jasna Kriz, Université Laval
  • A. Jane Roskams, University of British Columbia
  • Michael Smith Foundation for Health Research
  • Genome BC
  • University of British Columbia/Vancouver Coastal Health
  • Fonds de recherche du Quebec - Sante (FRQS)
  • Institut universitaire en sante mentale de Quebec (IUSMQ)

Project Overview

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 (motor neurons). The disease is characterized by systematic paralysis of the muscles of the limbs, speech, swallowing, and respiration, due to the progressive death of motor neurons. 30,000 individuals in North America are currently suffering from the disease; 2-3 Canadians are lost to ALS every day. Moreover, less than 20% of the affected individuals survive for longer than 5y after diagnosis. The disease is caused by a variety of inherited genetic mutations, but the vast majority of cases occur sporadically. ALS is currently incurable, though marginal disease-slowing is provided by the drug riluzole. Work by Dr. Cashman and his team, and others, have identified the importance of the three-dimensional shape of the copper-zinc superoxide dismutase-1 (SOD1) protein in the ALS disease process. This protein, when abnormally shaped, or misfolded, is prone to accumulate into a toxic form that can cause motor neuron death. Subsequently, these misfolded proteins are able to convert their normal counterparts into disease-causing forms; this process is believed to occur from cell to cell, eventually destroying muscle function. This disease mechanism has also been found in other neurological diseases, such as Alzheimer and Parkinson diseases. The team’s ultimate goal is to improve the treatment options for ALS patients. To achieve this goal, we herein propose a comprehensive research program that will greatly increase our understanding of the protein conversion process, its cell-to-cell spread, and how this translates to disease.