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The content provided discusses a study on the effects of the mutation of the ALS-/FTD-associated RNA-binding protein FUS on axonal development. The study found that mutants of FUS, namely FUS(P525L) and FUS(16R), significantly reduced axonal complexity in vivo in a Xenopus model of ALS/FTD. Furthermore, FUS(P525L) displayed an axon looping defect in the target area due to errors in stop cue signaling. The study also found that mutant FUS reduced actin density in the growth cone, altering its mechanical properties, potentially leading to defects during early axonal development.
Aberrant condensation and localization of the RNA-binding protein (RBP) fused in sarcoma (FUS) occur in variants of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Changes in RBP function are commonly associated with changes in axonal cytoskeletal organization and branching in neurodevelopmental disorders. Here, we asked whether branching defects also occur in vivo in a model of FUS-associated disease. We use two reported Xenopus models of ALS/FTD (of either sex), the ALS-associated mutant FUS(P525L) and a mimic of hypomethylated FUS, FUS(16R). Both mutants strongly reduced axonal complexity in vivo. We also observed an axon looping defect for FUS(P525L) in the target area, which presumably arises due to errors in stop cue signaling. To assess whether the loss of axon complexity also had a cue-independent component, we assessed axonal cytoskeletal integrity in vitro. Using a novel combination of fluorescence and atomic force microscopy, we found that mutant FUS reduced actin density in the growth cone, altering its mechanical properties. Therefore, FUS mutants may induce defects during early axonal development.