What Causes Motor Neurones To Die?

Our genetic code is over three billion letters long and holds the instructions for how to build everything in our bodies but in this form, it is nonsense. 'Editors' are therefore needed to copy, tidy and transport short sections of code, known as RNA, to produce instructions that can then be used to build new proteins. By studying the roles of TDP-43 and FUS, which have recently been identified as genetic causes of familial MND, researchers have found that they have a similar editing role. This therefore suggests that editors may play a potential role in the development of the disease.

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.

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.

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)

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 (Research Article 1-Nourishing Nutrition (1551 kb)). One form of motor neurone nutrients are a group of chemicals called neurotrophic factors, literally meaning “nerve nourishing factors”.

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) ).

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) .