MND Association-funded researchers, Prof Dame Kay Davies and Dr Peter Oliver, both based at the University of Oxford, have identified the oxidation resistance 1 (OXR1) gene as a neuroprotective factor in MND.
Published in the journal Brain on 9 March 2015, Prof Davies has shown through their recent research in mice that OXR1 may serve a new target for future drug development.
We’re funding Matthew Williamson’s PhD studentship to follow up this exciting research. Find out more about this and the other research projects funded by the Association in our newly updated Research we fund information sheet.
What causes MND? For the majority of cases, we know that it is a combination of subtle genetics, lifestyle and environmental factors, however, how they cause MND is harder to answer. A number of possible mechanisms have been identified as contributing to the death of motor neurones in MND. These include a buildup of toxic waste and harmful support cells (read more about these on our website here).
Researchers have also identified that ‘oxidative stress’ is another key process that causes motor neurones to die in MND.
Oxygen is an essential ingredient for producing energy; without this, our bodies would begin to shut down. However, too much of a good thing can be harmful, and the same is true for oxygen.
Our bodies build up ‘reactive oxygen species’, which are ‘types’ of oxygen that are extremely harmful to cells (including motor neurones).
Usually our bodies have antioxidants that ‘mop up’ these damaging oxygen species. However, in MND there seems to be an increase in the number of these oxygen species, which end up damaging the motor neurones (known as oxidative stress). The pathway that causes these oxygen species to increase in numbers has not yet been identified, however Prof Davies believes she has found a way to minimise the damage.
Oxidation Resistance 1 (OXR1) was initially identified as a gene that protects against nerve cell oxidative stress. In mice, loss of this gene results in oxidative damage and death of neurones, leading to a decrease in life expectancy.
OXR1 does not possess antioxidant scavenging properties (it is unable to mop up the excess reactive oxygen species). Instead, OXR1 causes neurones to be less susceptible to the damage caused by these oxygen species, essentially creating an anti-oxygen force field around the cells.
What the researchers found
Due to the ability of OXR1 to protect nerve cells from oxidative damage, Prof Davies wanted to find out if OXR1 was specifically able to protect the motor neurones in mouse models of MND.
By over expressing the OXR1 gene, Prof Davies found that OXR1 significantly increased survival and improved the symptoms of MND in these mice. The researchers found that not only did the mice survive longer; they also experienced an improvement in their symptoms.
The ability of OXR1 to slow down disease progression in mouse models of MND is the first step in potentially developing a new treatment for MND, and the researchers’ next steps will be to understand this process further and investigate whether this treatment has future therapeutic potential.
Prof Davies and co-grantee Dr Peter Oliver commented on this research: “One of the key questions in motor neurone disease (MND) research is why certain cells in the nervous system, motor neurons, are susceptible to degeneration over time, while other cell types are not. Oxidative stress has been implicated in MND as one of the early signs of this selective degeneration.”
“We have already shown that the gene oxidation resistance 1 (OXR1) can protect neurons from oxidative stress, and that loss of this gene renders cells more susceptible to a range of insults. We have now tested whether expressing more OXR1 in neurons could be protective in a mouse model of inherited MND. We were excited to discover that OXR1 could delay the motor deficits and motor neuron degeneration in a mouse MND model, as well as improve survival by up to 20%.
“This significant result suggests that OXR1 may be a valuable neuroprotective target for the future. We are currently working hard to understand the function of OXR1, with recent funding from The MND Association, to investigate how the gene can be regulated pharmacologically for future therapeutic benefit.”
More about this research
Prof Davies initial research has shown that increasing the levels of the gene OXR1 can protect motor neurones from death caused by oxidative stress, and delay MND in mice.
In October 2014 the Association awarded Prof Davies £95,826 as a PhD studentship to continue research into understanding more about the role of OXR1. PhD student Matthew Williamson will also aim to find out whether increasing levels of this gene could be a protective treatment approach (read more about this research and other research funded by the Association in our newly updated ‘Research we fund’ information sheet).
- Liu et al. 2015. Brain. DOI: http://dx.doi.org/10.1093/brain/awv039
- Video explaining this research: https://www.youtube.com/watch?v=44iLAv8C5UE
- Research we fund information sheet
Research involving animals: Approximately two thirds of the research projects we fund do not involve the use of animals. With those that do, we and the researchers we fund are committed to ensuring that the welfare of the animals is considered at all times. For more information on how we approach funding MND research involving animals, go to www.mndassociation.org/animalresearch.