Progress Update: Aberrant Protein Synthesis

Progress update by Sujatha Jagannathan

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 that may be generated from DUX4-induced aberrant RNAs as FSHD biomarkers.

During the 1-year funding period, we have 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, thus providing a snapshot of actively translated RNAs. Using this technology, we have confirmed that several aberrant RNAs are robustly translated in DUX4-expressing cells to produce potentially toxic proteins. We have characterized one of these aberrant proteins and shown that it exhibits cytotoxic effect on otherwise healthy muscle cells. We are continuing to characterize more aberrant proteins to understand how they contribute to FSHD pathogenesis. We are also in the process of generating custom antibodies that recognize a unique region in an aberrant protein that may be specific for FSHD and could be used as a biomarker.

See grant Deciphering the role of aberrant protein synthesis in FSHD