期刊
NATURE MEDICINE
卷 18, 期 9, 页码 1418-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.2901
关键词
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资金
- Flanders Institute for Biotechnology (VIB)
- University of Leuven [GOA 11/014]
- Life Sciences Research Partners, Research Foundation Flanders (FWO-Vlaanderen) [G.0695.10]
- Interuniversity Attraction Poles program of the Belgian Federal Science Policy Office [P7/16]
- Robert Packard Center for ALS Research
- Association Belge contre les Maladies Musculaires
- ALS League Belgium
- Thierry Latran Foundation
- European Community [259867]
- E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders at the University of Leuven
- Agency for Innovation by Science and Technology in Flanders (IWT-Vlaanderen)
- Research Fund KU Leuven
- Alfonso Martin Escudero Foundation
- UK National Institute for Health Research (NIHR) Dementia Biomedical Research Unit at South London
- King's College London
- US National Institute for Neurological Disease and Stroke (NINDS) [5RO1-NS050557-05]
- Angel Fund
- ALS Association
- Pierre L. de Bourgknecht ALS Research Foundation
- ALS Therapy Alliance
- Maudsley National Health Service (NHS) Foundation Trust
- NINDS American Recovery and Reinvestment Act Award [RC2-NS070-342]
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Disease onset and progression are variable, with survival ranging from months to decades. Factors underlying this variability may represent targets for therapeutic intervention. Here, we have screened a zebrafish model of ALS and identified Epha4, a receptor in the ephrin axonal repellent system, as a modifier of the disease phenotype in fish, rodents and humans. Genetic as well as pharmacological inhibition of Epha4 signaling rescues the mutant SOD1 phenotype in zebrafish and increases survival in mouse and rat models of ALS. Motor neurons that are most vulnerable to degeneration in ALS express higher levels of Epha4, and neuromuscular re-innervation by axotomized motor neurons is inhibited by the presence of Epha4. In humans with ALS, EPHA4 expression inversely correlates with disease onset and survival, and loss-of-function mutations in EPHA4 are associated with long survival. Furthermore, we found that knockdown of Epha4 also rescues the axonopathy induced by expression of mutant TAR DNA-binding protein 43 (TDP-43), another protein causing familial ALS, and the axonopathy induced by knockdown of survival of motor neuron 1, a model for spinomuscular atrophy. This suggests that Epha4 generically modulates the vulnerability of (motor) neurons to axonal degeneration and may represent a new target for therapeutic intervention.
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