RNA and FUS act in concert to prevent TDP-43 spatial segregation

FUS and TDP-43 are two self-adhesive aggregation-prone mRNA-binding proteins whose pathological mutations have been linked to neurodegeneration. While TDP-43 and FUS form reversible mRNA-rich compartments in the nucleus, pathological mutations promote their respective cytoplasmic aggregation in neurons with no apparent link between the two proteins except their intertwined function in mRNA processing. By combining analyzes in cellular context and at high-resolution in vitro , we unraveled that TDP-43 is specifically recruited in FUS assemblies to form TDP-43 rich sub-compartments but without reciprocity. The presence of mRNA provides an additional scaffold to promote the mixing between TDP-43 and FUS. Accordingly, we also found that the pathological truncated form of TDP-43, TDP-25, which has an impaired RNA binding ability, no longer mixes with FUS. Together, these results suggest that the binding of FUS along nascent mRNAs enables TDP-43, which is highly aggregation-prone, to mix with FUS phase in order to form mRNA-rich sub-compartments. A functional link between FUS and TDP-43 may explain their common implication in Amyotrophic Lateral Sclerosis (ALS).