Rare amyotrophic lateral sclerosis (ALS)-causing mutations clearly implicate ubiquitously expressed and predominantly nuclear RNA binding proteins (RBPs), which form pathological cytoplasmic inclusions in this context. However, it remains possible that RBPs can mislocalize without necessarily becoming constituents of cytoplasmic ALS inclusions. We hypothesized that nuclear-to-cytoplasmic mislocalization of the RBP Fused in Sarcoma (FUS), in an unaggregated state, may occur more widely in ALS

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... t previously recognized. To address this hypothesis, we analysed motor neurons (MNs) from human control and patient-specific VCP mutant induced-pluripotent stem cells (iPSCs), in addition to mouse transgenic models and post-mortem tissue from human sporadic ALS. We report nuclear-to-cytoplasmic mislocalization of FUS in both VCP-mutation related ALS and in sporadic ALS spinal cord tissue from multiple cases. In addition to finding evidence of associated DNA damage, we further link this mislocalization of FUS protein mechanistically to aberrant intron retention in the SFPQ transcript. Specifically, FUS protein binds extensively to the aberrantly retained intron within the SFPQ transcript, which is exported from the nucleus into the cytoplasm. Collectively, these data support a model whereby aberrant intron-retention in SFPQ transcripts contributes to FUS mislocalization through their direct interaction and nuclear export. In summary, we report widespread mislocalization of the FUS protein in ALS and propose a putative underlying mechanism for this process.