An international research group spanning seven countries and including 23 researchers has identified a gene that modifies survival in MND. The gene, called EPHA4 was identified through a zebrafish genetic screening project and verified in rodents and humans with MND. The study was led by Prof Wim Robberecht, who has previously been funded by the MND Association and who is the Chair of our International Symposium on ALS/MND. The findings were published in the prestigious journal Nature Medicine this week.
What did the research group find?
By screening zebrafish for genetic factors that can modify the progression of MND, the research group identified EPHA4. By stopping, or slowing down the activity of EPHA4, they identified that MND zebrafish can be rescued and rodents (mice and rats) can live longer.
They also identified that MND vulnerable motor neurones have a higher level of EPHA4 than those at a lesser risk of developing the disease. This also means that a low level of EPHA4 confers to a lower risk of MND.
The research group then looked to humans to see if anybody with MND had mistakes in the EPHA4 gene that resulted in a change in survival. The group found two people with MND with genetic differences in the EPHA4 gene. These two people lived with MND for an exceptionally long time. As these genetic differences result in a lower level of EPHA4, this suggests that EPHA4 could be a valid therapeutic target for MND.
What does EPHA4 do?
Ephrin type-A receptor 4 (EPHA4 for short), plays a vital role in the development of our nervous system, in maintaining the shape of the neurone and in preventing regeneration after injury.
As our motor neurones grow, the projecting length of the neurone (the axon) needs to be guided to grow toward the right areas to connect to its respective muscle. To do this, a complex ephrin negative signalling system is used to guide the growing neurone in the right direction.
In real life terms, this signalling pathway can be thought of as somebody blindfolded, navigating a traffic cone maze. This person (the neurone) doesn’t want to move into an area cornered off by traffic cones (the corresponding ephrin signal). As the neurone can’t see where it’s going, it feels its way around using Eph receptors like EPHA4. The neurone moves away from ephrin signals as it ‘feels’ them. This eventually leads to the neurone reaching its target destination (the muscle).
To physically make the neurone move, when an ephrin signal connects to the ephrin receptor, the inner workings of the neurone are called into action. To find out more information on this, please read our previous article about Profilin1, which was found to be a cause of MND last month.
As EPHA4 plays an integral role in stopping neurone growth, it isn’t surprising that it also plays a role in stopping regeneration of neurones after injury. For example, in mice that have spinal cord injury (this was a study unrelated to MND), by genetically stopping the EPHA4 signal, new axon growth can be seen. With mice that have spinal cord injury that have a normal level of EPHA4 signal, growth cannot be seen.
The above non-MND study, along with the current EPHA4 finding further suggests that a lower level of EPHA4 can result in a longer survival because of its inability to perform its usual function to its usual extent. This incompetance seemingly allows the protection of neurones from degenerating at it’s normal pace.
As an additional note, you may be thinking that it seems counterintuitive that humans have additional signals that stop processes like regeneration when less complex animals like frogs still have this ability. Unfortunately, it’s a bi-product of mammalian evolution that continues to baffle scientists!
What does this mean for people with MND?
This finding unfortunately does not mean that a new genetic test will become available for EPHA4.
This discovery does however, offer another target for research institutes to look into and develop therapies that could slow down disease progression by lowering the amount of EPHA4.
Although this research is likely to take years to develop toward a clinical trial* in humans, it’s promising to see yet another exciting genetic advance that could have an impact on finding a better treatment for MND in the future.
*It’s important to point out that therapeutically lowering the EPHA4 signal in humans would not necessarily mean that neurones could regenerate as seen in the zebrafish. Many different signals other than EPHA4 prevent a human motor neurone from regenerating and from finding its target muscle. However, finding a way to lower the EPHA4 signal may still slow down progression, as seen in mice in this study.
What does this mean for the future of MND research?
Further studies are needed to verify and expand on these exciting results.
This finding means that researchers can explore this pathway in more detail as it, in conjunction with the recent Profilin 1 finding, suggests that this guidance/growth system of motor neurones may play an important role in the development of MND.