Investigator: Sujatha Jagannathan PhD
Category: Research - Basic
When healthy muscle cells grown in the laboratory are forced to make the FSHD-causing protein DUX4, they die catastrophically. Studying these dying cells can offer a glimpse into the molecular events set in motion by DUX4 that culminate in cell death. Using engineered muscle cells that express DUX4 synchronously upon addition of a small molecule inducer, we propose to study the downstream consequences DUX4-mediated inhibition of an essential RNA quality control mechanism in the cell called NMD. Our hypothesis is that the translation of defective RNAs stabilized by DUX4 could flood the cell with defective and toxic protein products. In recent work supported by the Friends of FSH Research, we have identified such toxic protein products, and confirm their production in FSHD muscle. We have also characterized one of these aberrant proteins and shown that it exhibits cytotoxic effect on otherwise healthy muscle cells. Next, we are interested in: A) investigating the role of these aberrant RNAs in FSHD pathogenesis; and B) testing the utility of the unique protein products that may be generated from DUX4-induced aberrant RNAs as FSHD biomarkers. These studies will allow us to understand how misregulated RNA quality control contributes to FSHD pathogenesis, as well as leverage this phenomenon to generate FSHD-specific biomarkers.