eprintid: 10053380
rev_number: 32
eprint_status: archive
userid: 608
dir: disk0/10/05/33/80
datestamp: 2018-08-01 12:42:49
lastmod: 2021-09-17 22:20:27
status_changed: 2018-08-01 12:42:49
type: article
metadata_visibility: show
creators_name: Hock, E-M
creators_name: Maniecka, Z
creators_name: Hruska-Plochan, M
creators_name: Reber, S
creators_name: Laferrière, F
creators_name: Sahadevan M K, S
creators_name: Ederle, H
creators_name: Gittings, L
creators_name: Pelkmans, L
creators_name: Dupuis, L
creators_name: Lashley, T
creators_name: Ruepp, M-D
creators_name: Dormann, D
creators_name: Polymenidou, M
title: Hypertonic Stress Causes Cytoplasmic Translocation of Neuronal, but Not Astrocytic, FUS due to Impaired Transportin Function
ispublished: pub
divisions: UCL
divisions: B02
divisions: C07
divisions: D07
divisions: F86
keywords: ALS, FTD, FUS, RNA-binding proteins, Transportin, nucleocytoplasmic shuttling, protein aggregation, stress granules
note: © 2018 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
abstract: The primarily nuclear RNA-binding protein FUS (fused in sarcoma) forms pathological cytoplasmic inclusions in a subset of early-onset amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients. In response to cellular stress, FUS is recruited to cytoplasmic stress granules, which are hypothesized to act as precursors of pathological inclusions. We monitored the stress-induced nucleocytoplasmic shuttling of endogenous FUS in an ex vivo mouse CNS model and human neural networks. We found that hyperosmolar, but not oxidative, stress induced robust cytoplasmic translocation of neuronal FUS, with transient nuclear clearance and loss of function. Surprisingly, this reaction is independent of stress granule formation and the molecular pathways activated by hyperosmolarity. Instead, it represents a mechanism mediated by cytoplasmic redistribution of Transportin 1/2 and is potentiated by transcriptional inhibition. Importantly, astrocytes, which remain unaffected in ALS/FTD-FUS, are spared from this stress reaction that may signify the initial event in the development of FUS pathology.
date: 2018-07-24
date_type: published
official_url: https://doi.org/10.1016/j.celrep.2018.06.094
oa_status: green
full_text_type: pub
language: eng
primo: open
primo_central: open_green
article_type_text: Journal Article
verified: verified_manual
elements_id: 1571271
doi: 10.1016/j.celrep.2018.06.094
pii: S2211-1247(18)31036-2
lyricists_name: Gittings, Lauren
lyricists_name: Lashley, Tammaryn
lyricists_id: LMGIT29
lyricists_id: TJOHN05
actors_name: Flynn, Bernadette
actors_id: BFFLY94
actors_role: owner
full_text_status: public
publication: Cell Reports
volume: 24
number: 4
pagerange: 987-1000.e7
event_location: United States
issn: 2211-1247
citation:        Hock, E-M;    Maniecka, Z;    Hruska-Plochan, M;    Reber, S;    Laferrière, F;    Sahadevan M K, S;    Ederle, H;                             ... Polymenidou, M; + view all <#>        Hock, E-M;  Maniecka, Z;  Hruska-Plochan, M;  Reber, S;  Laferrière, F;  Sahadevan M K, S;  Ederle, H;  Gittings, L;  Pelkmans, L;  Dupuis, L;  Lashley, T;  Ruepp, M-D;  Dormann, D;  Polymenidou, M;   - view fewer <#>    (2018)    Hypertonic Stress Causes Cytoplasmic Translocation of Neuronal, but Not Astrocytic, FUS due to Impaired Transportin Function.                   Cell Reports , 24  (4)   987-1000.e7.    10.1016/j.celrep.2018.06.094 <https://doi.org/10.1016/j.celrep.2018.06.094>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10053380/1/1-s2.0-S2211124718310362-mmc2.pdf