EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans

• Published in: Nature medicine Vol. 18; no. 9; pp. 1418 - 1422
• Main Authors: Van Hoecke, Annelies, Schoonaert, Lies, Lemmens, Robin, Timmers, Mieke, Staats, Kim A, 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
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2012; Nature Publishing Group
• Subjects: 631/1647/334; 631/378/1689/1285; 692/420/2489/144; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - physiopathology; Analysis of Variance; Animal models; Animals; Base Sequence; Biomedical and Life Sciences; Biomedicine; Cancer Research; Danio rerio; Deoxyribonucleic acid; DNA; Gene Knockdown Techniques; Humans; Infectious Diseases; letter; Medical research; Metabolic Diseases; Mice; Mice, Knockout; Molecular Medicine; Molecular Sequence Data; Morpholinos - genetics; Motor Neurons - metabolism; Motor Neurons - pathology; Mutants; Mutation; Neurodegeneration; Neurons; Neurosciences; Phenotype; Rats; Receptor, EphA4 - metabolism; Rodents; Rotarod Performance Test; Sequence Analysis, DNA; Signal Transduction - physiology; Statistics, Nonparametric; Superoxide Dismutase - metabolism; Superoxide Dismutase-1; Survival; Zebrafish
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.2901

Epha4 is a receptor involved in axonal repulsion. Wim Robberecht and his colleagues report that genetic or pharmacological inhibition of Epha4 is protective in rodent and zebrafish models of amyotrophic lateral sclerosis. In humans, expression of Epha4 inversely correlates with disease onset and survival, and in two patients, mutations in Epha4 are associated with longer survival, suggesting Epha4 may be targeted therapeutically to prevent axonal degeneration. 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.