Hypertonic Stress Causes Cytoplasmic Translocation of Neuronal, but Not Astrocytic, FUS due to Impaired Transportin Function

Eva-Maria Hock, Zuzanna Maniecka, Marian Hruska-Plochan, Stefan Reber, Florent Laferrière, Sonu Sahadevan M.K., Helena Ederle, Lauren Gittings, Lucas Pelkmans, Luc Dupuis, Tammaryn Lashley, Marc-David Ruepp, Dorothee Dormann, Magdalini Polymenidou
Cell Reports. 2018-07-01; 24(4): 987-1000.e7
DOI: 10.1016/j.celrep.2018.06.094

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1. Cell Rep. 2018 Jul 24;24(4):987-1000.e7. doi: 10.1016/j.celrep.2018.06.094.

Hypertonic Stress Causes Cytoplasmic Translocation of Neuronal, but Not
Astrocytic, FUS due to Impaired Transportin Function.

Hock EM(1), Maniecka Z(1), Hruska-Plochan M(2), Reber S(3), Laferrière F(2),
Sahadevan M K S(1), Ederle H(4), Gittings L(5), Pelkmans L(2), Dupuis L(6),
Lashley T(5), Ruepp MD(7), Dormann D(4), Polymenidou M(8).

Author information:
(1)Institute of Molecular Life Sciences, University of Zurich,
Winterthurerstrasse 190, 8057 Zurich, Switzerland; Life Science Zurich Graduate
School, University of Zurich and ETH Zurich, Zurich, Switzerland.
(2)Institute of Molecular Life Sciences, University of Zurich,
Winterthurerstrasse 190, 8057 Zurich, Switzerland.
(3)Department of Chemistry and Biochemistry, University of Bern, Bern,
Switzerland; Graduate School for Cellular and Biomedical Sciences, University of
Bern, Bern, Switzerland.
(4)BioMedical Center (BMC), Ludwig-Maximiians-University Munich, 82152
Planegg-Martinsried, Germany; Graduate School of Systemic Neurosciences (GSN),
82152 Planegg-Martinsried, Germany; Munich Cluster for Systems Neurology
(SyNergy), 81377 Munich, Germany.
(5)Queen Square Brain Bank for Neurological Diseases, Department of Molecular
Neuroscience, UCL Institute of Neurology, London WC1N 1PJ, UK.
(6)Faculty of Medicine, INSERM UMR-S1118 and Fédération de Médecine
Translationnelle, Université de Strasbourg, Strasbourg, France.
(7)UK Dementia Research Institute Centre at King’s College London, Institute of
Psychiatry, Psychology and Neuroscience, King’s College London, Maurice Wohl
Clinical Neuroscience Institute, 125 Coldharbour Lane, London SE5 9NU, UK.
(8)Institute of Molecular Life Sciences, University of Zurich,
Winterthurerstrasse 190, 8057 Zurich, Switzerland; Life Science Zurich Graduate
School, University of Zurich and ETH Zurich, Zurich, Switzerland. Electronic
address: .

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.

Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

DOI: 10.1016/j.celrep.2018.06.094
PMID: 30044993

Auteurs Bordeaux Neurocampus