What Causes Motor Neurones To Die?

Painstaking research has provided evidence of disruption to many processes within the cellular 'infrastructure' of motor neurones and their support cells. This has parallels with the infrastructure within our towns and cities, for example: efficient energy production, a decent transport system, communication networks and regular refuse collections are all requirements for healthy motor neurones.
EM of neurone

Disruption to chemical communication networks

In the spinal cord the electrical message is transmitted from one motor neurone to the next via the release of a chemical messenger in the gap between them. For many motor neurones this chemical messenger is glutamate but at high concentrations glutamate can be toxic. The cause of its toxicity is still under investigation in MND laboratories around the world. Riluzole, the only approved treatment for MND, is thought to work by suppressing glutamate activity.


Transport disruption

Motor neurones are large cells; the largest can be up to a metre long. It is therefore important that their transport systems for moving nutrients, waste and components from one end to the other work well. Research suggests that in MND, the transport system gets disrupted very early on in the disease process. A better understanding of transport disruption could point researchers towards new ways of treating MND.

Aggravating aggregation

Abnormal clumps (aggregates) of protein molecules are found inside motor neurones affected by MND and may disrupt their normal functioning. Proteins normally stick together when they are faulty - the mutated SOD1 molecules found in some cases of familial MND stick together in this way. In 2006, researchers found that a protein called TDP-43 is found in the clumps seen in most cases of MND; in 2008, a research group at King’s College London established evidence that faulty TDP-43 plays a role in damaging motor neurones. Stopping faulty molecules from sticking together or enhancing the neurone’s ability to clear them away are possible strategies for treating MND.

s banner in lab

Cleaning up toxic waste

Oxygen free radicals are toxic chemicals formed as a normal by-product of processes within the cell. They are normally mopped up by antioxidants, but research suggests that in MND, the motor neurones’ own antioxidant defence pathways may be suppressed. Returning these defences to their full efficiency could be one way of treating MND.

The possible role of oxygen free radicals in MND has led to a number of studies investigating whether antioxidants may be beneficial to people with MND (Research Information sheet K- Antioxidants (81 kb)


Power failure

All cells contain tiny “batteries” called mitochondria, which are responsible for producing energy for the cell and also play other key roles in maintaining the cell’s normal function. The mitochondria in motor neurones from people with MND appear abnormal. They may be damaged by oxidative stress and glutamate toxicity.

A Grierson in lab

Nourishing the nerves

Many of the theories that contribute to motor neurone death are about cellular processes that become disrupted. There is some evidence that motor neurones become more susceptible to MND because of the lack of nutrients. One form of motor neurone nutrients are a group of chemicals called neurotrophic factors, literally meaning “nerve nourishing factors”. A clinical trial of one these, Myotrophin (also known as Insulin like growth factor 1) is currently underway in North America.

A number of unsuccessful clinical trials have already investigated this group of chemicals in MND. None of these trials have led to new drugs, however lessons have been learnt that will lead to better trials in the future (Research Information sheet H - Lessons from Neurotrophic Factor clinical trials (118 kb) ).


Problem neighbours

Motor neurones are surrounded by cells called glia, which normally provide the neurones with support and nourishment. However, researchers have now come to realise that glial cells can in fact contribute to motor neurone degeneration - they may lose their supportive properties and can even become toxic. Glia might therefore make a good target for new drugs for MND. You can read more about the involvement of glial cells in Research Article 16 - Motor Neurone Neighbourhood Watch (792 kb) .

More information

Research article 13 - Piecing together the jigsaw (1594 kb) gives more information on these theories on why motor neurones die in MND. Some of these ideas are under investigation in the Research the Association is funding (see also Research Information sheet E - Funding MND research (153kb) )