Investigating the processes that prevent neural damage is one way of ameliorating the most devastating aspects of MS. “Eph4 is a molecule present during adult brain injury and appears to be a major player in stopping neural repair after brain injury,” says Dr Ann Turnley.
EphA4 is thought to be involved in the development of MS scars – the areas a neurologist will typically point out on a MS brain MRI - and stopping the regeneration of neural tissue to replace that damaged during MS. Figure 1 shows the abundance of EphA4 around a mouse spinal cord lesion.
Dr Turnley will produce MS-like disease in a special animal model that is missing the gene that encodes for EphA4. This will allow the assessment of the severity and progression of the disease to see if the absence of EphA4 can improve the clinical outcomes. Preliminary studies indicate that the mice that are missing the EphA4 gene develop less severe symptoms in the MS-like model.
“We will eventually also try different treatments to see if blocking EphA4 activity in animals that are not missing the EphA4 gene can improve outcomes” adds Dr Turnley. If this research shows improvements in mice it could lead to a new drug target to explore in human studies.
A nerve growth regulatory molecule, EphA4, is normally found during development of the brain, but is also found in adult brain disease or injury. It regulates regrowth of nerves and the response of cells called astrocytes that form a scar. Associate Professor Ann Turnely’s research examines the role of EphA4 in the severity of and recovery from the mouse model of MS called EAE.
EphA4 was found on astrocytes in EAE lesions, similar to a report that showed it on astrocytes in human MS lesions. EAE was examined in normal and mice that did not have the EphA4 gene (EphA4 knockout mice) to identify differences. Onset of clinical signs commenced similarly for both types of mice but the disease was more severe in normal mice. Therefore, the clinical course of EAE does not appear to be as severe in the EphA4 knockout mice.
Analysis of spinal cords from diseased mice showed a typical inflammatory infiltrate in both normal and EphA4 knockout mice and there was no significant difference in the number of lesions per section. However, a test that measures the level of a protein in the blood that indicates nerve damage indicated that EphA4 knockout mice had lower levels, suggesting that they may have had less nerve damage.
Overall, these results suggest that blocking of the EphA4 signal could be a therapeutic strategy for MS, by reducing the damage produced by inflammation rather than inflammation itself. As a first step, Associate Professor Turnley are now exploring options to achieve this blocking effect in the mouse model of MS.
Updated: 03 January, 2008