Targeting Stress Granule Biology in Alzheimer’s Disease

The function of RNA is to help translate the genetic “blueprint” of DNA information into actual proteins that execute the majority of functions in a cell.  RNA binding proteins (RBPs) regulate the conversion of messenger RNA to protein through formation of complexes called RNA granules. Chemical stresses induce formation of a particular type of complex termed the stress granules (SG).  Our preliminary data showed that the neurofibrillary tangles that accumulate in Alzheimer’s disease (AD) are associated with SGs. We hypothesized that the process of aggregation associated with SGs might actually stimulate pathology in AD.  The BrightFocus Foundation was the first organization to give us funding for this project.  Using BrightFocus funds we made the startling finding that tau protein is actually required for SG responses, which means that the pathological changes driving AD are intimately connected to the SG response.  We also showed that SG formation stabilizes tau protein, stimulates tau misfolding, and stimulates formation of the insoluble tau that forms the pathology of AD.  Equally importantly, we showed that removing a SG protein (TIA-1) actually prevents the misfolding of tau associated with AD.  This suggests that reducing SG formation might be a novel therapeutic strategy for AD.   We are pushing this work forward on three fronts. 1) We are determining if reducing TIA1 inhibits tau pathology and disease progression, and 2) we have identified the proteins that associate with the tau – SG complex, and will be determining which are most important for disease progression.  Finally, we are deeply grateful to BrightFocus Foundation because funding from the foundation allowed us to get preliminary data that we have used to get multiple other grant awards.