Reducing EphA4 before disease onset does not affect survival in a mouse model of Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons resulting in severe neurological symptoms. Previous findings of our lab suggested that the axonal guidance tyrosine-kinase receptor EphA4 is an ALS disease-modifying gene. Reduction of EphA4 from developmental stages onwards rescued a motor neuron phenotype in zebrafish, and heterozygous deletion before birth in the SOD1^G93A mouse model of ALS resulted in improved survival. Here, we aimed to gain more insights in the cell-specific role of decreasing EphA4 expression in addition to timing and amount of EphA4 reduction. To evaluate the therapeutic potential of lowering EphA4 later in life, we ubiquitously reduced EphA4 levels to 50% in SOD1^G93A mice at 60 days of age, which did not modify disease parameters. Even further lowering EphA4 levels ubiquitously or in neurons, did not improve disease onset or survival. These findings suggest that lowering EphA4 as target in ALS may suffer from a complex therapeutic time window. In addition, the complexity of the Eph-ephrin signalling system may also possibly limit the therapeutic potential of such an approach in ALS. We suggest here that a specific EphA4 knockdown in adulthood may have a limited therapeutic potential for ALS.