Progress Update: Deciphering the role of aberrant protein synthesis in FSHD

Report by Dr. Jagannathan
See Grant Deciphering the role of aberrant protein synthesis in FSHD

In the FSHD muscle, cells are flooded with aberrant and potentially harmful RNA molecules due to a lack of quality control caused by the expression of DUX4. Our lab is interested in: A) investigating the role of these aberrant RNAs in FSHD pathogenesis, and B) testing the utility of the unique protein products generated from DUX4-induced aberrant RNAs as FSHD biomarkers.

In previous work funded by Friends of FSH Research we established a highly complex procedure called “ribosome footprinting” that reads out the bits of RNA contained within molecular machines called ribosomes that are actively engaged in translating RNAs into proteins, and used this technology to confirm that several aberrant RNAs are robustly translated in DUX4-expressing cells to produce potentially toxic proteins. During the current 6-month funding period, we optimized and validated the experimental systems required to knock out aberrant RNAs encoding truncated proteins in an isoform-specific manner and began the experiments that will allow us to determine their necessity for DUX4 toxicity