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EMBO J. 2016 May 17;35(10):1077-97. doi: 10.15252/embj.201592559. Epub 2016 Mar 7.

Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss.

Author information

1
Faculté de Médecine, INSERM U1118, Strasbourg, France Université de Strasbourg UMR_S1118, Strasbourg, France.
2
Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine, Muenster, Germany Faculty of Medicine, University of Muenster, Muenster, Germany.
3
Department of Neurosciences, University of California, San Diego La Jolla, CA, USA Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA, USA.
4
Institut Clinique de la souris, Illkirch-Graffenstaden, France.
5
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
6
University of Cardiff, Cardiff, UK.
7
Department of Neurology University of Ulm, Ulm, Germany.
8
Mammalian Cell Signaling Laboratory, Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Muenster, Germany.
9
Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine, Muenster, Germany Faculty of Medicine, University of Muenster, Muenster, Germany erik.storkebaum@mpi-muenster.mpg.de clagier-tourenne@mgh.harvard.edu ldupuis@unistra.fr.
10
Department of Neurosciences, University of California, San Diego La Jolla, CA, USA Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA, USA erik.storkebaum@mpi-muenster.mpg.de clagier-tourenne@mgh.harvard.edu ldupuis@unistra.fr.
11
Faculté de Médecine, INSERM U1118, Strasbourg, France Université de Strasbourg UMR_S1118, Strasbourg, France erik.storkebaum@mpi-muenster.mpg.de clagier-tourenne@mgh.harvard.edu ldupuis@unistra.fr.

Abstract

FUS is an RNA-binding protein involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cytoplasmic FUS-containing aggregates are often associated with concomitant loss of nuclear FUS Whether loss of nuclear FUS function, gain of a cytoplasmic function, or a combination of both lead to neurodegeneration remains elusive. To address this question, we generated knockin mice expressing mislocalized cytoplasmic FUS and complete FUS knockout mice. Both mouse models display similar perinatal lethality with respiratory insufficiency, reduced body weight and length, and largely similar alterations in gene expression and mRNA splicing patterns, indicating that mislocalized FUS results in loss of its normal function. However, FUS knockin mice, but not FUS knockout mice, display reduced motor neuron numbers at birth, associated with enhanced motor neuron apoptosis, which can be rescued by cell-specific CRE-mediated expression of wild-type FUS within motor neurons. Together, our findings indicate that cytoplasmic FUS mislocalization not only leads to nuclear loss of function, but also triggers motor neuron death through a toxic gain of function within motor neurons.

KEYWORDS:

FUS; PY‐NLS; amyotrophic lateral sclerosis; frontotemporal dementia; motor neuron degeneration

PMID:
26951610
PMCID:
PMC4868956
DOI:
10.15252/embj.201592559
[Indexed for MEDLINE]
Free PMC Article

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