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

Eva-Maria Hock, 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.
Zuzanna Maniecka, 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.
Marian Hruska-Plochan, Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Stefan Reber, Department of Chemistry and Biochemistry, University of Bern, Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
Florent Laferrière, Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Sonu Sahadevan M K, 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.
Helena Ederle, 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.
Lauren Gittings, Queen Square Brain Bank for Neurological Diseases, Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 1PJ, UK.
Lucas Pelkmans, Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Luc Dupuis, Faculty of Medicine, INSERM UMR-S1118 and Fédération de Médecine Translationnelle, Université de Strasbourg, Strasbourg, France.
Tammaryn Lashley, Queen Square Brain Bank for Neurological Diseases, Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 1PJ, UK.
Marc-David Ruepp, 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.
Dorothee Dormann, 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.
Magdalini Polymenidou, 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: magdalini.polymenidou@imls.uzh.ch.

Document Type

Article

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.

Keywords

ALS, FTD, FUS, RNA-binding proteins, Transportin, nucleocytoplasmic shuttling, protein aggregation, stress granules

Medical Subject Headings

Animals; Astrocytes (metabolism); Cell Nucleus (metabolism); Cerebral Cortex (cytology, metabolism); Cytoplasm (metabolism); HEK293 Cells; Hippocampus (cytology, metabolism); Humans; Karyopherins (metabolism); Mice; Mice, Inbred C57BL; Neurons (metabolism); RNA-Binding Protein FUS (metabolism); Transfection

Publication Date

7-24-2018

Publication Title

Cell reports

E-ISSN

2211-1247

Volume

24

Issue

4

First Page

987

Last Page

1000.e7

PubMed ID

30044993

Digital Object Identifier (DOI)

10.1016/j.celrep.2018.06.094

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