Discovery of Therapeutic Targets for FUS- and TDP43-Dependent Forms of ALS
- Peter St. George-Hyslop, University of Toronto
- Mei Zhen, Lunenfeld-Tanenbaum Research Institute, Mount Sinani Hospital
- Peter Roy, University of Toronto
- Ben Wolozin, Boston University
- Clemens Kaminski, University of Cambridge
- ALS Society of Canada
The four most commonly studied ALS proteins are SOD1, TDP-43, FUS and C9ORF72. Of these, TDP-43 and FUS have the most in common. Not only do they share similar functions inside cells, but in motor neurons of people with ALS, they both accumulate in clumps outside of the area where they are supposed to perform their normal function (called the nucleus). A team led by Dr. Peter St George-Hyslop, professor at the University of Toronto and Director of the Tanz Centre for Research in Neurodegenerative Diseases will aim to understand if altering specific FUS clumps (called ribonucleoprotein granules or RNPs) through a variety of approaches can have a therapeutic effect in ALS. First, the team will use worms called Caenorhabditis elegans that contain multiple different abnormalities in the FUS gene to search through thousands of drugs for compounds that can decrease the number of FUS RNPs and a follow up examination if any of these then improve the disease symptoms including reducing paralysis and increasing worm lifespan. Simultaneously, they will perform a method called genome wide mutagenesis, which will look for genetic changes that can alter FUS RNP levels and toxicity. Validation of drugs that reduce FUS RNP formation and toxicity will be further done in various cell types with mutant FUS including mouse and frog motor neurons and those derived from human induced pluripotent stem (iPS) cells. The team will also test positive drugs for their ability to directly affect the mechanism of RNP granule formation in a tube. Finally, the most promising compounds will be tested in a FUS mouse model to determine their effects on the disease. Should any prove effective, Dr. St George-Hyslop’s group aims to establish partnerships with a biotech/pharma company to immediately move them forward to clinical trials in humans.