Inducible EphA4 knockout causes motor deficits in young mice and is not protective in the SOD1G93A mouse model of ALS

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.

Effects of lncRNA HOXA11-AS on Sevoflurane-Induced Neuronal Apoptosis and Inflammatory Responses by Regulating miR-98-5p/EphA4

“…Studies have also found that during the development of the neuronal system, EphA4 plays a crucial role in axon guidance [ 31 , 32 ] and can also directly act on motor neurons to cause cell death [ 30 ]. Current studies have shown that EphA4 inhibitors have neuroprotective effects on Alzheimer's disease, spinal cord injury, and stroke in mouse models [ 33 ]. Our study found that double-luciferase results indicate that miR-98-5 targets EphA4; EphA4 is highly expressed in the neuronal cells induced by sevoflurane and the hippocampus of animal models ( Figure 5 ).…”

EphA4 targeting agents protect motor neurons from cell death induced by amyotrophic lateral sclerosis -astrocytes

“…Preliminary studies in the SOD1(G93A) mouse model demonstrated that the heterozygous deletion of the EphA4 gene before birth improved survival (Van Hoecke et al, 2012). However, follow-up studies showed that 50% ubiquitous reduction of EphA4 at symptom onset did not improve survival (Dominguez et al, 2020;Rue et al, 2019b;Zhao et al, 2018). This suggests that the reduction of EphA4 levels is not sufficient to provide a therapeutic benefit.…”