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Acta Neuropathol. 2017 Jun;133(6):887-906. doi: 10.1007/s00401-017-1687-9. Epub 2017 Feb 28.

Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis.

Author information

1
Inserm, UMR-S1118, 67085, Strasbourg, France.
2
Faculté de Médecine, UMR-S1118, Université de Strasbourg, 67085, Strasbourg, France.
3
Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine, Muenster, Germany.
4
Faculty of Medicine, University of Muenster, Muenster, Germany.
5
Department of Neurosciences, Ludwig Institute for Cancer Research, University of California, San Diego, USA.
6
BioMedical Center (BMC), Cell Biology, Ludwig-Maximilians-Universität München, Munich, Germany.
7
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
8
BioMedical Center (BMC), Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany.
9
German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany.
10
Department of Neurology, Ulm University, Ulm, Germany.
11
Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, 02129, USA.
12
Broad Institute of Harvard University and MIT, Cambridge, MA, 02142, USA.
13
Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine, Muenster, Germany. erik.storkebaum@mpi-muenster.mpg.de.
14
Faculty of Medicine, University of Muenster, Muenster, Germany. erik.storkebaum@mpi-muenster.mpg.de.
15
Inserm, UMR-S1118, 67085, Strasbourg, France. ldupuis@unistra.fr.
16
Faculté de Médecine, UMR-S1118, Université de Strasbourg, 67085, Strasbourg, France. ldupuis@unistra.fr.

Abstract

Motor neuron-extrinsic mechanisms have been shown to participate in the pathogenesis of ALS-SOD1, one familial form of amyotrophic lateral sclerosis (ALS). It remains unclear whether such mechanisms contribute to other familial forms, such as TDP-43 and FUS-associated ALS. Here, we characterize a single-copy mouse model of ALS-FUS that conditionally expresses a disease-relevant truncating FUS mutant from the endogenous murine Fus gene. We show that these mice, but not mice heterozygous for a Fus null allele, develop similar pathology as ALS-FUS patients and a mild motor neuron phenotype. Most importantly, CRE-mediated rescue of the Fus mutation within motor neurons prevented degeneration of motor neuron cell bodies, but only delayed appearance of motor symptoms. Indeed, we observed downregulation of multiple myelin-related genes, and increased numbers of oligodendrocytes in the spinal cord supporting their contribution to behavioral deficits. In all, we show that mutant FUS triggers toxic events in both motor neurons and neighboring cells to elicit motor neuron disease.

KEYWORDS:

Amyotrophic lateral sclerosis; Fronto-temporal dementia; Mouse models; Non-cell autonomous mechanisms; RNA-binding proteins

PMID:
28243725
PMCID:
PMC5427169
DOI:
10.1007/s00401-017-1687-9
[Indexed for MEDLINE]
Free PMC Article

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