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.