Posted by Friends of FSH Research on Sep 24, 2020
Board member and researcher Dr. Premi Haynes interviews grant recipient Dr. Sujatha Jagannathan.
See grant Deciphering the role of aberrant protein synthesis in FSHD
What made you decide to pursue research in FSHD?
My entry into FSHD research was quite serendipitous. I did my PhD in Cell Biology at Duke University where I studied ways in which fundamentally important biological molecules called messenger RNAs (mRNAs), which carry the information to produce all proteins in the cell, were regulated. For my postdoctoral fellowship, I wished to continue studying this molecule but in the context of disease. During my search, I learned about the work of Drs. Stephen Tapscott and Robert Bradley about how misregulation of an mRNA quality control process was involved in regulating the stability of DUX4 mRNA and this got me interested in FSHD. As I learned more about FSHD and how poorly understood the mechanisms of its pathogenesis were, I became fascinated by the biological puzzle that it offered. I was quickly convinced I should pursue my postdoctoral research in this area. I am grateful that I made this decision not only because FSHD continues to be a fertile ground for mRNA research, but also because I have come to truly appreciate the scientific and patient community around FSHD and value the satisfaction that comes from knowing that I could contribute to bring us closer to our collective goal of finding a cure for FSHD.
What is Nonsense Mediated Decay (NMD)?
Nonsense Mediated mRNA Decay, or NMD, is essentially a garbage disposal mechanism that cells use to eliminate bad mRNAs that encode faulty proteins. To understand this process, we need to consider the flow of genetic information in the cells. DNA which contain the genetic blueprint of every cell, is copied on to disposable mRNA molecules which in turn serve as templates to make proteins – the functional molecules that often define what a cell is. If there is a mistake in an mRNA, the cells cannot produce a functional protein. In fact, it might produce a harmful protein that could be toxic to the cells. NMD is a mechanism that protects against this eventuality by identifying bad mRNAs by looking for certain cues that tell them that a given mRNA would not produce a functional protein, and then eliminating them. In cells that express DUX4, the FSHD-causing protein, NMD stops working, and cells accumulate hundreds of such bad mRNAs.
What made you connect NMD to some of the molecular level pathogenesis of FSHD?
The original discovery that DUX4 inhibits NMD was made by two people in the Bradley and Tapscott laboratories: Qing Feng, a graduate student at the time in the Bradley lab, and Lauren Snider, a Staff Scientist at the time in the Tapscott lab. I was fortunate to join their team at the time and I contributed to the study by discovering the mechanism by which DUX4 inhibits NMD (Feng et al., eLife, 2015). We knew then that by inhibiting NMD, DUX4 was engaging a feedback loop that helped amplify its own mRNA, thus contributing to FSHD pathogenesis. After we published this discovery, I began looking at the downstream effects of NMD inhibition by DUX4 and how this might contribute to FSHD pathogenesis. Through this investigation, I found that upon NMD inhibition the cells accumulated not just bad mRNAs but also faulty proteins that could be harmful to the DUX4-expressing cells and contribute to their death and ultimately the pathogenesis of FSHD.
What are the toxic proteins and how do you detect them?
Many of the toxic proteins that appear to be produced in FSHD are themselves RNA binding proteins. You can detect them by using existing reagents and looking for a “truncated protein” or generate custom reagents that will only detect the truncated protein specifically. We are attempting both of these approaches in the lab currently.
How do you envision this funded work by Friends of FSH research will help in identification of a Biomarker and or/therapeutics for FSHD?
Many of the potentially “toxic” proteins produced due to NMD inhibition by DUX4 have parts that might be uniquely observed only in FSHD patients that we believe can be leveraged as FSHD biomarkers. In terms of therapeutics, we are also pursuing ways in which we can prevent the production of such toxic proteins and whether this would rescue the cell health of DUX4-expressing cells. We have a long way to go, but we believe this could offer a complementary way to develop an FSHD therapeutic that is independent of inhibiting DUX4 or interfering with its production.