The study by Van Hoecke et al. not only identifies EphA4 as a potential therapeutic target for amyotrophic lateral sclerosis (ALS), but it also reveals an unexpected role of this receptor tyrosine kinase in determining the disease duration of ALS. The authors show that reduction of EphA4 expression rescues motor axonopathy and significantly prolongs the survival of the SOD1 mutant mice, an ALS mouse model. Importantly, the beneficial effect of inhibiting EphA4 in slowing down the disease progression in these mice is verified by administration of EphA4 inhibitors. Intriguingly, they also demonstrate that the relative EphA4 expression in the blood of ALS patients is inversely correlated with the age of disease onset, and two EphA4 variants are identified in patients associated with uncharacteristically long survival. These observations together unequivocally indicate that EphA4 is a critical determinant of ALS disease progression and open a new avenue in ALS research.

The study is remarkable in a number of aspects. First, it demonstrates the success of using lower vertebrates,...  Read more

The study by Van Hoecke et al. not only identifies EphA4 as a potential therapeutic target for amyotrophic lateral sclerosis (ALS), but it also reveals an unexpected role of this receptor tyrosine kinase in determining the disease duration of ALS. The authors show that reduction of EphA4 expression rescues motor axonopathy and significantly prolongs the survival of the SOD1 mutant mice, an ALS mouse model. Importantly, the beneficial effect of inhibiting EphA4 in slowing down the disease progression in these mice is verified by administration of EphA4 inhibitors. Intriguingly, they also demonstrate that the relative EphA4 expression in the blood of ALS patients is inversely correlated with the age of disease onset, and two EphA4 variants are identified in patients associated with uncharacteristically long survival. These observations together unequivocally indicate that EphA4 is a critical determinant of ALS disease progression and open a new avenue in ALS research.

The study is remarkable in a number of aspects. First, it demonstrates the success of using lower vertebrates, such as zebrafish, as a model system to screen for signaling molecules that are crucial for the progression of neurodegenerative diseases. Second, it identifies EphA4 as the key player in regulating motor neuron survival, thus revealing the therapeutic potential of EphA4 inhibitors in ALS. It would be of interest to examine whether downstream effectors of EphA4 such as α2-chimaerin are involved in the disease as well (Dalva, 2007; Shi et al., 2007). Finally, findings from this study raise the intriguing possibility of using pharmacological inhibitors of EphA4 as a therapeutic strategy for neurodegenerative diseases. Our laboratory and others have demonstrated that EphA4 is a key negative regulator of neurotransmission in the brain by promoting dendritic spine retraction and degradation of neurotransmitter receptors (Murai et al., 2003; Fu et al., 2007; Fu et al., 2011). Since deficits in synaptic transmission and plasticity are associated with neurodegenerative diseases such as Alzheimer’s disease, EphA4 inhibitors might represent promising therapeutic agents for these diseases.

References:
Dalva MB (2007) There's More than One Way to Skin a Chimaerin. Neuron 55:681-684. Abstract

Fu AK, Hung KW, Fu WY, Shen C, Chen Y, Xia J, Lai KO, Ip NY (2011) APC(Cdh1) mediates EphA4-dependent downregulation of AMPA receptors in homeostatic plasticity. Nat Neurosci 14:181-189. Abstract

Fu WY, Chen Y, Sahin M, Zhao XS, Shi L, Bikoff JB, Lai KO, Yung WH, Fu AK, Greenberg ME, Ip NY (2007) Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism. Nat Neurosci 10:67-76. Abstract

Murai KK, Nguyen LN, Irie F, Yamaguchi Y, Pasquale EB (2003) Control of hippocampal dendritic spine morphology through ephrin-A3/EphA4 signaling. Nat Neurosci 6:153-160. Abstract

Shi L, Fu WY, Hung KW, Porchetta C, Hall C, Fu AK, Ip NY (2007) Alpha2-chimaerin interacts with EphA4 and regulates EphA4-dependent growth cone collapse. Proc Natl Acad Sci U S A 104:16347-16352. Abstract

View all comments by Nancy Ip

This is a seminal study showing that EphA4 expression in motor neurons is an important factor in animal models of ALS and, critically, that reduced EphA4 expression correlates with less severe disease in humans.

When we developed the EphA4-/- mouse, it revealed the crucial role of this protein in motor axons. We thus predicted an important role in neurological diseases affecting motor nerves. In this study by Van Hoecke et al., it was not possible to use the EphA4-/- animals, but the EphA4+/- x SOD1 cross had significantly slowed ALS disease progression. Thus, inhibitors which reduce EphA4 function to less than 50 percent would be predicted to slow disease to at least this extent. We have recently reported a positive therapeutic effect of an EphA4 inhibitor on motor function after spinal cord injury (Goldshmit et al., 2011), and therefore strongly support the suggestion that such agents may have a beneficial role in ALS.

References:
Goldshmit Y, Spanevello MD, Tajouri S, Li L, Rogers F, Pearse M, Galea M, Bartlett PF, Boyd AW, Turnley AM. EphA4 blockers promote axonal regeneration and functional recovery following spinal cord injury in mice. PLoS One. 2011;6(9):e24636. Abstract

View all comments by Andrew Boyd