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

Abstract

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
Cytoplasm
DNA Damage
Mice, Transgenic
Motor Neurons
RNA-Binding Proteins
Binding Protein
Mutant
Drug Retention

Related Feeds

BioRxiv & MedRxiv Preprints

BioRxiv and MedRxiv are the preprint servers for biology and health sciences respectively, operated by Cold Spring Harbor Laboratory. Here are the latest preprint articles (which are not peer-reviewed) from BioRxiv and MedRxiv.

Amyloid Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a progressive nervous system disease associated with the death of neurons that control voluntary muscles. Discover the latest research on ALS here.