title: EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans.
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.
authors.affiliation: Laboratory of Neurobiology, Vesalius Research Center, VIB, Leuven, Belgium.
authors.forename: Annelies
authors.initials: A
authors.lastname: Van Hoecke
authors.forename: Lies
authors.initials: L
authors.lastname: Schoonaert
authors.forename: Robin
authors.initials: R
authors.lastname: Lemmens
authors.forename: Mieke
authors.initials: M
authors.lastname: Timmers
authors.forename: Kim A
authors.initials: KA
authors.lastname: Staats
authors.forename: Angela S
authors.initials: AS
authors.lastname: Laird
authors.forename: Elke
authors.initials: E
authors.lastname: Peeters
authors.forename: Thomas
authors.initials: T
authors.lastname: Philips
authors.forename: An
authors.initials: A
authors.lastname: Goris
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Dubois
authors.forename: Peter M
authors.initials: PM
authors.lastname: Andersen
authors.forename: Ammar
authors.initials: A
authors.lastname: Al-Chalabi
authors.forename: Vincent
authors.initials: V
authors.lastname: Thijs
authors.forename: Ann M
authors.initials: AM
authors.lastname: Turnley
authors.forename: Paul W
authors.initials: PW
authors.lastname: van Vught
authors.forename: Jan H
authors.initials: JH
authors.lastname: Veldink
authors.forename: Orla
authors.initials: O
authors.lastname: Hardiman
authors.forename: Ludo
authors.initials: L
authors.lastname: Van Den Bosch
authors.forename: Paloma
authors.initials: P
authors.lastname: Gonzalez-Perez
authors.forename: Philip
authors.initials: P
authors.lastname: Van Damme
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
authors.forename: Leonard H
authors.initials: LH
authors.lastname: van den Berg
authors.forename: Wim
authors.initials: W
authors.lastname: Robberecht
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000503:physiopathology*; D000704:Analysis of Variance; D000818:Animals; D001483:Base Sequence; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D060172:Morpholinos / Q000235:genetics; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D051381:Rats; D036122:Receptor, EphA4 / Q000378:metabolism*; D045442:Rotarod Performance Test; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000502:physiology*; D018709:Statistics, Nonparametric; D013482:Superoxide Dismutase / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D015027:Zebrafish
chemical_list: D060172:Morpholinos; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D036122:Receptor, EphA4