New gene linked to ALS severity

EphA4 receptor associated with more aggressive illness

An international team of researchers, including a Packard scientist, has identified a new gene linked to the severity of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease. Wim Robberecht, a Packard-funded researcher and neuroscientist at the University of Leuven in Belgium, and colleagues have discovered that blocking the receptor known as EphA4 increases survival in fish and rodent models of ALS. The study, published August 26 in Nature Medicine, also found that human ALS patients with the most EphA4 receptors had the earliest age of onset and the lowest survival times.

"EphA4 helps determine the severity of ALS," Robberecht said. "If someone is going to get ALS, the more of this protein that he or she expresses, the younger they will be at age of onset, and they will have a shorter disease duration."

Wim Robberect

ALS, also known as Lou Gehrig's Disease, affects approximately 30,000 Americans. Most are diagnosed in their 50s or 60s, and most live for an average of 2 to 5 years after diagnosis. These averages, however, conceal a wide variability in both age of onset and duration of illness. Patients have been diagnosed with ALS everywhere from their 20s to their 80s, and can live for anywhere from a few months to a decade or more.

This wide variability in ALS severity made Robberecht wonder what, if any, genetic factors might be involved in determining when the disease began and how long it lasted. To do this, he screened over 300 genes in a zebrafish model of ALS and found that when he blocked the expression of one of these genes, the zebrafish lived longer. This gene was Rtk2, which is very similar to human EphA4.

When Robberecht and colleagues repeated these experiments in mice and rats, they had the same results: blocking the action of EphA4 increased survival in animals carrying a mutation in SOD1. Looking closer, the researchers found that the large motor neurons had the most EphA4 mRNA (which translates the EPHA4 gene into protein), and are the most vulnerable to degeneration in ALS. In contrast, small motor neurons have fewer copies of EphA4 mRNA and their degeneration occurs only at end-stage disease. As well, the presence of EphA4 prevented damaged motor neurons from re-innervating muscle. Together, these results indicate that EphA4 plays an important role in motor neuron degeneration.

Together with Bob Brown, a P2ALS researcher at the University of Massachusetts Medical School,  Robberecht and colleagues then looked at the potential role of EphA4 in human ALS patients and found that patients with the highest EphA4 expression had the most severe course of disease. They showed symptoms at an earlier age and tended to survive for a shorter period of time after diagnosis. Those ALS patients whose EphA4 proteins didn't function properly survived much longer than patients with functional EphA4.

Because EphA4 is a receptor protein, Robberecht said, that means that it should be possible to find small molecules binding to it. Finding a molecule that can inhibit the action of EphA4 might be a potential therapeutic target for improving the lifespan of patients diagnosed with ALS, he noted.