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

Healthy muscle cells forced to make the FSHD-causing protein DUX4 die through processes we do not yet fully understand. We are studying the downstream consequences of DUX4- mediated inhibition of an essential RNA quality control pathway in the cell called NMD. We hypothesize that in DUX4-expressing cells, truncated proteins produced from aberrant RNAs that can no longer be degraded by NMD flood the cell with defective and toxic protein products.

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. In the current funding period, we developed various experimental systems and protocols to study these toxic proteins. Despite unforeseen technical challenges, we characterized a specific truncated protein by showing that it is present in FSHD patient-derived muscle cells and that reducing its expression can rescue cells from DUX4-mediated cell death.