Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron loss that ultimately leads to fatal paralysis. Reducing levels or function of the tyrosine kinase, ephrin type-A receptor 4 (EphA4), has been suggested as a potential approach for slowing disease progression in ALS. Because EphA4 plays roles in embryonic nervous system development, study of constitutive knockout (KO) of EphA4 in mice is limited due to confounding phenotypes with homozygous knockout. We used a tamoxifen-inducible EphA4 conditional KO mouse to achieve strong reduction of EphA4 levels in postnatal mice to test for protective effects in the SOD1G93A model of ALS. We found that EphA4 KO in young mice, but not older adult mice, causes defects in muscle function, consistent with a prolonged postnatal role for EphA4 in adolescent muscle growth. When testing the effects of inducible EphA4 KO at different timepoints in SOD1G93A mice, we found no benefits on motor function or disease pathology, including muscle denervation and motor neuron loss. Our results demonstrate deleterious effects of reducing EphA4 levels in juvenile mice and do not provide support for the hypothesis that widespread EphA4 reduction is beneficial in the SOD1G93A mouse model of ALS.
Highlights
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron loss that leads to fatal paralysis
To test the level of ephrin type-A receptor 4 (EphA4) depletion that could be achieved with tamoxifen induction, adult EphA4 Cre + mice were placed on either tamoxifen or control diet for 4 weeks, after which mRNA levels were tested via quantitative polymerase chain reaction
The tamoxifen-fed group showed an average of 87% reduction of EphA4 mRNA (Fig. 1a) and near complete reduction was observed in the brain (Fig. 1b)
Summary
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron loss that leads to fatal paralysis. That study found benefits of reducing EphA4 in rodent models of ALS, including preserved spinal cord motor neurons, increased neuromuscular junction (NMJ) innervation, and improved survival with heterozygous EphA4 KO in the superoxide dismutase 1 (SOD1G93A) mouse model[2]. A different study found that CNS reduction of EphA4 levels with antisense oligonucleotides delivered directly to the central nervous system starting at 49 days of age had no benefit for motor function or survival in two ALS models, including SOD1G93A mice[9]. Because EphA4 is repulsive to axon growth and plays roles in spinal circuit formation during early d evelopment[11], constitutive homozygous KO results in abnormalities in motor function, limiting previous studies to examining the effects of heterozygous KO (i.e., 50% reduction in EphA4) in SOD1G93A mice. We find no evidence for a protective role of EphA4 KO in S OD1G93A mice
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