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GEN News Highlights : Aug 27, 2012
Target Discovered for ALS
Scientists have identified a new therapeutic target for the neurodegenerative disease amyotrophic lateral sclerosis (ALS). The target, a receptor known as Epha4, was identified by researchers at the University of Leuven in Belgium through a screen for genes involved in preventing activity of the causative SOD1 mutation in a zebrafish model of ALS. Notably, Epha4 appears to work in conjunction with Profiiln-1, a gene identified as a potential target for ALS by collaborating investigators at the University of Massachusetts Medical School, who reported on their work just last month.
The latest Epha4 research is described by a team headed by the University of Leuven's Wim Robberecht, Ph.D., and Annelies Van Hoecke, Ph.D, who found that knocking down the zebrafish gene Rtk2 in mutant-SOD1 zebrafish completely rescued the motor axonopathy induced by different SOD1 mutations. Rtk2 is the zebrafish paralog of the human gene Epha4, a member of the A subclass of Eph receptor tyrosine kinases that interacts with A-type and B-type ephrins.
When the researchers then knocked out one copy of the Epha4 gene in a mouse model of ALS that overexpresses a human mutant SOD1, they found the animals exhibited much better motor performance and lived much longer than ALS mice carrying both copies of Epha4. Interestingly, the single-knockout animals didn’t start to develop disease any later, but they did survive longer after ALS became manifest, and displayed slower motor neuron degeneration. In fact survival after disease onset was increased by 57%, and the rate of motor performance deterioration was reduced by 40% in the single-knockout animals.
Encouragingly, similarly beneficial effects in terms of rescuing mutant SOD1-induced axonopathy were obtained in the mouse model by chemically inhibiting Epha4, whereas ALS model given intraracerebroventricular treatment with an Epha4-blocking peptide demonstrated delayed disease onset and prolonged survival. In effect, deleting one Epha4 gene slows disease progression, whereas pharmacological inhibition delayed onset. The researchers say this difference may relate to the differences between the rat and mouse models, or to the different strategies. One deletes the gene at the embryonic stage, whereas the other knocks out the protein in adult life.
Interestingly, when the team looked at Epha4 expression in a genetic association study of nearly 3,000 ALS patients and over 9,000 controls, they found that lower Epha4 mRNA expression correlated with later disease onset. A multiple regression analysis including age at onset as a prognostic factor also highlighted a similar correlation between lower Epha4 expression and prolonged disease duration, which appears to support the notion that the protective effect of low Epha4 expression affects both age at onset and disease progression.
The researchers then sequenced the Epha4 gene in patients with ALS and identified two previously unknown coding variants that were associated with the patients demonstrating much longer than expected survival. One of the mutations is a nonsense mutation resulting in protein truncation, the other is a missense mutation that generates a full-length protein with impaired signalling function.
In a final set of experiments, the investigators showed that as well as acting to block the ALS-causing effects of SOD1 mutation in animal models, genetic knockdown, or pharmacological inhibition of Epha4 in zebrafish prevented axonopathy resulting from expression of another mutant protein, TDP-43, and also blocked the motor axon abnormalities caused by deletion of Smn1, a zebrafish model used to study spinal muscular atrophy. These findings suggest that the protective effect of Epha4 receptor inhibition is actually independent of the cause of degeneration, the investigators write in Nature Medicine. Rather, it seems that the ephrin system may be a generic determinant of vulnerability of neurons to degeneration. “This suggests that Epha4 generically modulates the vulnerability of (motor) neurons to axonal degeneration and may represent a new target for therapeutic intervention ... Although this is a proof-of-concept study, the finding that pharmacological inhibition of Epha4 affects models of ALS suggests that interference with this system may be an avenue for preclinical research in both familial and sporadic ALS.”
The published paper by Dr. Robberecht et al., is titled “Epha4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans.”
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