10779/crick.11559840.v1 Giulia E Tyzack Giulia E Tyzack Raphaelle Luisier Raphaelle Luisier Doaa M Taha Doaa M Taha Jacob Neeves Jacob Neeves Miha Modic Miha Modic Jamie S Mitchell Jamie S Mitchell Ione Meyer Ione Meyer Linda Greensmith Linda Greensmith Jia Newcombe Jia Newcombe Jernej Ule Jernej Ule Nicholas M Luscombe Nicholas M Luscombe Rickie Patani Rickie Patani Widespread FUS mislocalization is a molecular hallmark of amyotrophic lateral sclerosis. The Francis Crick Institute 2020 RNA binding protein amyotrophic lateral sclerosis (ALS) fused in sarcoma FUS intron retention Patani - sec Luscombe FC001110 Ule - sec Neurology & Neurosurgery 11 Medical and Health Sciences 17 Psychology and Cognitive Sciences 2020-01-09 16:45:11 Journal contribution https://crick.figshare.com/articles/journal_contribution/Widespread_FUS_mislocalization_is_a_molecular_hallmark_of_amyotrophic_lateral_sclerosis_/11559840 Mutations causing amyotrophic lateral sclerosis (ALS) clearly implicate ubiquitously expressed and predominantly nuclear RNA binding proteins, which form pathological cytoplasmic inclusions in this context. However, the possibility that wild-type RNA binding proteins mislocalize without necessarily becoming constituents of cytoplasmic inclusions themselves remains relatively unexplored. We hypothesized that nuclear-to-cytoplasmic mislocalization of the RNA binding protein fused in sarcoma (FUS), in an unaggregated state, may occur more widely in ALS than previously recognized. To address this hypothesis, we analysed motor neurons from a human ALS induced-pluripotent stem cell model caused by the VCP mutation. Additionally, we examined mouse transgenic models and post-mortem tissue from human sporadic ALS cases. We report nuclear-to-cytoplasmic mislocalization of FUS in both VCP-mutation related ALS and, crucially, in sporadic ALS spinal cord tissue from multiple cases. Furthermore, we provide evidence that FUS protein binds to an aberrantly retained intron within the SFPQ transcript, which is exported from the nucleus into the cytoplasm. Collectively, these data support a model for ALS pathogenesis 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.