Abstract
Motor neuron disease (MND) comprises a group of fatal neurodegenerative diseases with no effective cure. As progressive motor neuron cell death is one of pathological characteristics of MND, molecules which protect these cells are attractive therapeutic targets. Accumulating evidence indicates that EphA4 activation is involved in MND pathogenesis, and inhibition of EphA4 improves functional outcomes. However, the underlying mechanism of EphA4’s function in MND is unclear. In this review, we first present results to demonstrate that EphA4 signalling acts directly on motor neurons to cause cell death. We then review the three most likely mechanisms underlying this effect.
Highlights
Motor neuron disease (MND) refers to a group of neurodegenerative diseases, which have the shared characteristic of the progressive loss of upper and/or lower motor neurons [1,2]
Given the substantial loss of induced motor function in this model, these results suggest that mEphA4-Fc is a promising therapeutic treatment for MND and EphA4 activation is involved in the disease pathogenesis [22]
The results showed that heterozygous deletion of EphA4 in motor neurons significantly increased the number of surviving motor neurons in the spinal cord of the SOD1G93A mice, compared to the homozygous deletion group or normal SOD1G93A mice at 17 weeks of age
Summary
Motor neuron disease (MND) refers to a group of neurodegenerative diseases, which have the shared characteristic of the progressive loss of upper and/or lower motor neurons [1,2]. We generated a wildtype EphA4-Fc (a recombinant fusion protein derived from the extracellular domain of wildtype EphA4 and the Fc domain of human IgG) which effectively blocks EphA4ephrin interaction in vitro and demonstrated that it improves functional performance in mice and rats after SCI by increasing the number of axons reaching and crossing the lesion site compared with saline-treated controls [18,19,23]. Results of the toxicokinetic analysis of human mEphA4-Fc cells in healthy Sprague-Dawley rats following 5× weekly repeat intravenous dosing showed that the terminal elimination half-life ranged from 52.8 h to 77.5 h Using this glycosylation mutant of mouse mEphA4-Fc in the SOD1G93A model significantly improved motor performance, including rotarod and hind-limb grip strength tests [22]. Given the substantial loss of induced motor function in this model, these results suggest that mEphA4-Fc is a promising therapeutic treatment for MND and EphA4 activation is involved in the disease pathogenesis [22]
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