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RGNEF modulates protein misfolding in ALS

Principal Investigator:
  • Martin L. Duennwald, University of Western Ontario
  • ALS Society of Canada

Project Overview

Discoveries made in Canada by the lab of Dr. Michael Strong over the past few years have implicated a protein called Rho guanidine nucleotide exchange factor (RGNEF) both pathologically and genetically in causing ALS. Further study demonstrated that RGNEF could play a role in the abnormal shape (misfolding) and toxicity of two of the four most prominent ALS proteins called TDP-43 and FUS. Dr. Martin Duennwald, assistant professor at Western University will lead a study in collaboration with Dr. Alex Parker at Université de Montréal to examine whether or not RGNEF protects motor neurons against misfolded TDP-43 and FUS, as well as their subsequent toxicity. If it does, Dr. Duennwald then aims to determine the specific mechanism of action, primarily through focusing on a particular region called the GEF domain, which could also demonstrate RGNEF as an intriguing target for therapy. To perform these experiments the duo has developed unique worm models (C. elegans) that lack RGNEF both in the presence and absence of mutant TDP-43 and FUS. The team will also use yeast and mammalian cells to confirm their findings. At present, studies on RGNEF’s role in ALS are uniquely being pursued by these London teams and confirmation of Dr. Duennwald’s hypothesis will undoubtedly create a stronger international focus on this potentially important protein.