ALS and SMA: Less EPHA4 Means More Motor Neurons Survive

by Amy Madsen on Mon, 2012-09-03 05:00

Decreased activity of the EPHA4 receptor leads to extended life span in animal models of ALS and SMA, and in people with ALS

Article Highlights:
  • In zebrafish, inhibition of the EPHA4 receptor rescues motor neuron abnormalities caused by mutations in the ALS-associated SOD1 and TDP43 genes, and in the spinal muscular atrophy gene SMN1.
  • Limited activity of the EPHA4 receptor is associated with decreased severity of symptoms, later onset and increased life span in people with ALS.
  • Therapies designed to block EPHA4 activity potentially could modify the disease course of ALS and SMA.

Decreased activity of the EPHA4 receptor, which is encoded by the EPHA4 gene, increases life span in people with amyotrophic lateral sclerosis (ALS), a team of scientists has reported.

The receptor, which was found to modify disease in zebrafish, mice, rats and humans, works together with a gene recently associated with ALS — profilin 1 (PFN1).  

When investigators inhibited EPHA4 receptor signaling using either genetic or drug strategies, symptoms were eliminated in zebrafish, and survival time increased in mouse and rat models of ALS.

The new findings suggest that interfering with EPHA4 "may be an avenue for preclinical research in both familial and sporadic ALS," the researchers note.

EPHA4 in ALS models

Wim Robberecht at University Hospital Leuven in Leuven, Belgium, and colleagues, identified the EPHA4 receptor as a genetic modifier of the ALS disease process in a zebrafish model of ALS caused by mutations in the SOD1 gene.

When the team "knocked down" (reduced production of) the receptor in the zebrafish, the disease did not occur.

Decreasing EPHA4 activity by 50 percent in the SOD1 ALS mouse model slowed degeneration of motor neurons (nerve cells that control muscle activity, which are destroyed in ALS), reduced the rate of motor function deterioration by 40 percent, and increased life span by 57 percent.

Treatment designed to block EPHA4 in an SOD1 ALS rat model delayed disease onset and increased survival.

EPHA4 in people with ALS

In people with ALS, a link was established between EPHA4 receptor activity and disease course, with lower levels of EPHA4 correlating with later disease onset, a milder disease process and longer survival time.

Two people with ALS who have limited receptor activity caused by mutations in the EPHA4 gene were identified by the study team. Both had longer survival times after onset (seven years, four months, and 12 years, five months) than those with more EPHA4 receptor activity.

EPHA4 levels higher in large motor neurons

In further studies, the researchers found that:

  • larger motor neurons are more susceptible to damage in ALS than smaller motor neurons;
  • larger motor neurons express higher levels of the EPHA4 receptor; and
  • EPHA4 activity prevented these neurons from recovering from damage. 

The protective effect of knocking down EPHA4 in mice was most pronounced in large motor neurons.

EPHA4 and TDP43, SMN1

Also in zebrafish, the investigators examined the effect of EPHA4 on motor neuron degeneration caused by mutations in the ALS-associated gene TDP43 and in the SMN1 gene. (A deficiency of the SMN protein encoded by the SMN1 gene causes spinal muscular atrophy, or SMA, another disease in which motor neurons are lost.)

They found that genetic and drug inhibition of the EPHA4 receptor rescued motor neuron abnormalities caused by mutations in both the TDP43 and SMN1 genes.

These observations suggest that the protective effect of inhibition of the EPHA4 receptor is independent of the cause of degeneration, the researchers noted.

The new findings were published online Aug. 26, 2012, in Nature Medicine. See EPHA4 is a Disease Modifier of Amyotrophic Lateral Sclerosis in Animal Models and in Humans for the article preview.

Two studies identify the same pathway

In a related development, an MDA-supported team of researchers led by John Landers, associate professor of neurology, and Robert Brown, professor and chair of neurology, both at the University of Massachusetts Medical School in Worcester, identified a gene called profilin 1 (PFN 1) as a cause of familial ALS in study results published July 15, 2012.

PFN1 and EPHA4 work together as part of the same molecular pathway in motor neurons that has now been directly linked both to ALS susceptibility and severity.

“Taken together, these findings are particularly exciting because they suggest that suppression of EPHA4 may be a new way to treat ALS,” Brown said in a University of Massachusetts Medical School communication.

The findings also may have implications for treatment of SMA.

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