TY - JOUR
T1 - Hypertonic Stress Causes Cytoplasmic Translocation of Neuronal, but Not Astrocytic, FUS due to Impaired Transportin Function
AU - Hock, Eva-Maria
AU - Maniecka, Zuzanna
AU - Hruska-Plochan, Marian
AU - Reber, Stefan
AU - Laferrière, Florent
AU - Sahadevan M K, Sonu
AU - Ederle, Helena
AU - Gittings, Lauren
AU - Pelkmans, Lucas
AU - Dupuis, Luc
AU - Lashley, Tammaryn
AU - Ruepp, Marc-David
AU - Dormann, Dorothee
AU - Polymenidou, Magdalini
N1 - Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
PY - 2018/7/24
Y1 - 2018/7/24
N2 - 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.
AB - 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.
U2 - 10.1016/j.celrep.2018.06.094
DO - 10.1016/j.celrep.2018.06.094
M3 - Article
C2 - 30044993
SN - 2211-1247
VL - 24
SP - 987-1000.e7
JO - Cell Reports
JF - Cell Reports
IS - 4
ER -