Progress Update: Defining the role of PTM on FSHD protein DUX4

Posted by Friends of FSH Research on Sep 29, 2019

Update by Jocelyn O Eidahl PhD

FSHD is caused when the toxic DUX4 protein is turned on in muscle cells. When DUX4 is turned on, it can cause cell death, leading to muscle weakness over time. Many proteins in our cells do not exist as one species. In fact, they can be temporarily modified on their surfaces and these changes can affect how they behave. As an analogy to this process, think of a wrench that you would use to tighten a bolt. If you wrapped the head of the wrench with heavy tape, you would have difficulties using it for its intended purpose. Since taping the wrench is not a permanent change, you could remove the tape and have a functional wrench again. Proteins can behave in a similar fashion. Their surfaces can be modified at different locations, and these modifications can change their function.

In this study, we wanted to test our theory that the surface of the DUX4 protein could be modified in cells, and that these surface changes could affect whether or not it was toxic to those cells. We set out to look for those modifications in the initial stages of this study, and we indeed found some surface modifications on the DUX4 protein. In the past year, we used some molecular techniques to determine if those surface changes could impact DUX4 toxicity in cells on a dish. We found that most of them did not – regardless of whether or not those changes were present, DUX4 was still toxic to cells. However, we found 3 surface changes on the DUX4 protein that did impact its ability to cause cell death. Importantly, we found a drug that was able to prevent the addition of one of these surface changes to the DUX4 protein, and by doing so, it made DUX4 non-toxic. We will now explore this compound further to determine if could be useful for protecting muscles from DUX4 damage in mice. We hope that this work will someday soon lead to a therapy for FSHD by providing a new class of drugs that could be useful for treating the disease.

See grant Defining the role of post-translational modification on FSHD protein DUX4