Fig. 5. Proposed model of mutant FUS cytoplasmic gain of function.

Under control conditions (left), low levels of FUS are present in the cytoplasm and the phase separation of FUS and FMRP are at a physiological equilibrium. Loss of FUS (middle) results in a reduction of FMRP association with the translational machinery; however, this does not induce significant alterations in FMRP LLPS or global protein translation. In FUS-ALS (right), the increased cytoplasmic localization of FUS shifts the LLPS equilibrium of both FUS and FMRP, resulting in an increase in cytoplasmic condensates. This is associated with a depletion of the proteins from the translational machinery and an overall decrease in protein synthesis.