Hot Protein: FUS bucket
Remember the ice bucket challenge? Sure, it was a great way to rapidly refresh on a balmy summer day while producing a short video that could make you a short-lived Facebook trend. However, the challenge had the far more noble purpose of raising money and awareness for amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. The hallmark of this disease is the continuous deterioration of one’s ability to move until death, which occurs 3-5 years after diagnosis. Genetics alone accounts for only about 10% of the cases. The causes of the other 90% of cases are unknown and the subject of many research projects.
Interestingly, 3 to 5% of the ALS cases known to be genetic in origin have mutations in the “Fused in sarcoma/ translocated in liposarcoma” (FUS/TLS or FUS) gene. With the ability to bind DNA, RNA and other proteins, the unique protein FUS may participate in many crucial cellular functions. It has been implicated in regulating RNA synthesis, repairing broken DNA strands, and regulating telomeres (DNA at end of chromosome that shortens with age). Although it is not completely understood how FUS binds to RNA, research demonstrates that FUS may contribute in messenger RNA (mRNA) processing, the localization of mRNA within the cell and be associated in the translation of mRNA into protein.
Recent research has shown that the mutant FUS protein localizes more to the cytoplasm and associates more with stress granules (cytoplasmic aggregates of RNA and protein that form in response to metabolic or environmental stresses). These stress granules act as holding facilities for mRNA that were actively being translated into protein, but halted. What the cell requires to return to homeostasis will largely affect the fate of the stalled translation complexes. The mutant FUS affects the dynamics, increases the size, and boosts the number of stress granules. In deceased ALS patients, markers for the granules have been observed. It has been postulated that the stress granule build up serves as the forerunner for the aggregates detected at the end-stage of ALS.
Aside from stress granules, dysfunctional FUS can influence the development of ALS in other ways.
Many of the FUS mutations correlated with ALS occur in FUS’s DNA-binding sites. These mutations could alter FUS’s role in DNA repair. It is also plausible that FUS’s role in telomere biology might be impaired by these mutations or by a different set of mutations. If the DNA damage builds up or telomeres erode too quickly, it can lead to cell death. This finding does not bode well for the majority neurons that do not replicate because it would imply that they will not last very long.
Although it may sound like we know almost everything that is needed to know about FUS, we still see only the very tip of the iceberg. Are there factors other than genetics that can cause FUS to go rogue and lead to a sporadic case of ALS? Only with more research will we get closure to fully understanding the underlying causes of this debilitating/ deadly disease, and douse it with an appropriate and effective cure.
Sama, R. R., Ward, C. L., & Bosco, D. A. (2014). Functions of FUS/TLS from DNA repair to stress response: implications for ALS. ASN Neuro, 6(4). doi:10.1177/1759091414544472