DOI: 10.1101/491787Apr 9, 2019Paper

Widespread FUS mislocalization is a molecular hallmark of ALS

BioRxiv : the Preprint Server for Biology
Giulia E. TyzackRickie Patani


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 that 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 cytopl...Continue Reading

Related Concepts

Amyotrophic Lateral Sclerosis
Cell Nucleus
DNA Damage
Mice, Transgenic
Motor Neurons
RNA-Binding Proteins
Binding Protein
Drug Retention

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