Regulation of the stress granule proteome and transcriptome by TDP-43 in ALS: biomarkers and therapeutic targets
- Christine Vande Velde, Université de Montréal
- Avi Chakrabartty, University of Toronto
- Guy Rouleau, Montreal Neurological Hospital and Institute
- Michael Strong, University of Western Ontario
- ALS Society of Canada
When cells are under stress, one of the reactions is to form tiny clumps called stress granules that protect important genetic information while protective mechanisms kick in. Toxicity in ALS might arise from both an abnormal ability to properly form stress granules and/or a failure to disassemble stress granules after formation resulting in important life substances being locked away. In ALS, a number of the disease-causing genes that have been discovered encode proteins that are involved in stress granule pathways, including TAR DNA–binding protein 43 (TDP-43), which is abnormally clumped up in the majority of cases. For this project, Dr. Christine Vande Velde and her team will fully characterize stress granules using preliminary data demonstrating that TDP-43 is a key mediator in their composition and regulation. Through looking at motor neurons in the absence or presence of both normal and mutant, disease-causing TDP-43, they will first examine stress granule content, assembly and disassembly in laboratory cells through high powered methods. In addition to the standard substances expected to be captured in stress granules (protein and RNA), the team will also explore a novel effect of TDP-43 and stress granules on substances called microRNA (miRNA), which are less understood and have increasing connection to ALS.