ALS-associated mutations in FUS disrupt the axonal distribution and function of SMN

Mutations in theRNAbinding protein fused in sarcoma/translated in liposarcoma (FUS/TLS) cause amyotrophic lateral sclerosis (ALS). AlthoughALS-linkedmutations inFUSoften lead to acytosolicmislocalization of the protein, the pathogenic mechanisms underlying these mutations remain poorly understood. To gain insight into thesemechanisms, weexaminedthe biochemical, cell biologicalandfunctional properties ofmutantFUSinneurons. Expression of different FUS mutants (R521C, R521H, P525L) in neurons caused axonal defects. A protein interaction screen performed to explain these phenotypes identified numerous FUS interactors including the spinal muscular atrophy (SMA) causing protein survival motor neuron (SMN). Biochemical experiments showed that FUS and SMN interact directly and endogenously, and that this interaction can be regulated by FUS mutations. Immunostaining revealed co-localization of mutant FUS aggregates and SMN in primary neurons. This redistribution of SMN to cytosolic FUS accumulations led to a decrease in axonal SMN. Finally, cell biological experiments showed that overexpression of SMN rescued the axonal defects induced by mutant FUS, suggesting that FUS mutations cause axonal defects through SMN. This study shows that neuronal aggregates formedbymutantFUSproteinmayaberrantly sequesterSMNandconcomitantly cause a reductionofSMN levels in the axon, leading to axonal defects. These data provide a functional link between ALS-linkedFUS mutations, SMN and neuronal connectivity and support the idea that different motor neuron disorders such as SMA and ALS may be caused, in part, by defects in shared molecular pathways.

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