A protein called FUS is involved in several important biochemical reactions inside human cells, including in the synthesis of new proteins from genetic material. FUS can be found in several different physical states: fully dissolved state, phase separated liquid protein droplets like oil and vinegar or phase separated hydrogel states like bits of jelly floating in a liquid. These states play a significant role in the cellular processes in which FUS is involved. Importantly, when these processes go awry, they can trigger diseases such as frontotemporal lobar degeneration (FTLD). Therefore, understanding the molecular and cellular factors that control the transition of the FUS protein from one physical state to another, called phase separation, would be invaluable and could yield avenues for therapeutic interventions in FTLD.
In this study funded in part by CCNA and led by Dr. Peter St George-Hyslop and his team, working in collaboration with several scientists from the UK, Spain and the USA, the researchers uncovered several key elements implicated in the phase separation of the FUS protein. By reconstituting and manipulating key steps of the separation process in the laboratory and using atomic force nano-infrared spectroscopy to visualize the state of the protein, they found that the phase separation of FUS is very tightly regulated by the chemical structure of some specific amino acids forming the protein. They also uncovered the role of another protein, TNPO1, which appears to not function properly in some cases of FTLD. When these processes are deregulated, the FUS protein condenses into irreversible hydrogels in neurons. This results in the shutdown of the synthesis of new proteins in synapses (junctions between nerve cells).
These results are important because they provide some clues as to why in FTLD, the FUS protein was found to accumulate in some neurons. Importantly several methods developed to conduct this study will be useful tools to further study FUS phase separation and its effects on FTLD, and to search for treatments/preventions of these currently incurable diseases.
Authors: Qamar S., Wang G., Randle S.J., Ruggeri F.S., Varela J.A., Lin J.Q., Phillips E.C., Miyashita A., Williams D., Strohl F., Meadows W., Ferry R., Dardov V.J., Tartaglia G.G., Farrer L.A., Kaminski Schierle G.S., Kaminski C.F., Holt C.E., Fraser P.E., Schmitt-Ulms G., Klenerman D., Knowles T., Vendruscolo M., St George-Hyslop P.