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Title: EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans
Authors: Van Hoecke, Annelies
Schoonaert, Lies
Lemmens, Robin
Timmers, Mieke
Staats, Kim
Laird, Angela S
Peeters, Elke
Philips, Thomas
Goris, An
Dubois, Bénédicte
Andersen, Peter M
Al-Chalabi, Ammar
Thijs, Vincent
Turnley, Ann M
van Vught, Paul W
Veldink, Jan H
Hardiman, Orla
Van Den Bosch, Ludo
Gonzalez-Perez, Paloma
Van Damme, Philip
Brown, Robert H
van den Berg, Leonard H
Robberecht, Wim # ×
Issue Date: Sep-2012
Publisher: Nature Pub. Co.
Series Title: Nature Medicine vol:18 issue:9 pages:1418-1422
Abstract: 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.
URI: 
ISSN: 1078-8956
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory for Neuroimmunology
Laboratory for Neurobiology (Vesalius Research Center)
× corresponding author
# (joint) last author

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