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.

A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism

“…Here, we dissect the two proposed gain-of-function mechanisms in an in vivo zebrafish model for C9 ALS. This model is similar to previously established ALS zebrafish models [29,31] which have generated robust, relevant and translational insights into the pathogenesis of ALS [47].…”

The phenotypic variability of amyotrophic lateral sclerosis

“…107 Polymorphisms in the UNC13A gene and expression levels of EPHA4 have been suggested to contribute to the variability in disease severity. 106,109 ATXN2 expansions are a risk factor for ALS but not for FTD, 90 whereas the TMEM106B risk allele is a risk factor for FTD but not for ALS. 110 Phenotypic variability across the ALS-FTD spectrum (and probably other spectra) is, thus, believed to be largely due to various genetic polymorphisms with different cytotoxic or cytoprotective effects according to neuronal cell type.…”

“…The size of the motor neurons, the length of their axons, their metabolic rate and many other characteristics have been hypothesized as contributors, but never proven to have a role. Some evidence suggests that the low abundance of calcium buffering proteins 104 and the presence of mitochondrial matrix metalloproteinase-9 105 underlie the difference in vulnerability between oculomotor and other motor neurons.Expression of the ephrin type-A receptor 4 protein (encoded by EPHA4), 106 as well as excitability characteristics, 107 have been suggested to contribute to the difference in vulnerability of large versus small motor neurons. Susceptibility of motor neurons to excito toxi city could explain why spinal sensory neurons are less vulnerable to ALS than are motor neurons.…”

Modifications of a Nanomolar Cyclic Peptide Antagonist for the EphA4 Receptor To Achieve High Plasma Stability

“…[4][5][6][7]10 KYL has been administered in animal models by continuous infusion into the brain or spinal cord with minipumps. 4,6,10 However, this invasive route of administration has limited applicability in the clinic.…”