Genetic link for motor neurone disease

The Independent reports that for “only the second time in more than a century” researchers have made discoveries about the nature of amyotrophic lateral sclerosis (ALS), a disease affecting motor neurones that is usually fatal. Scientists have identified mutations in the gene responsible for the TDP-43 protein in people with ALS, a protein that is known to build up in the nerves (neurones) of people with ALS. This is “likely to be the reason why the neurones eventually die”, the newspaper said. About 5,000 people in the UK are reported to have ALS, including the renowned scientist Steven Hawking.

This research increases the understanding of the genetic basis of this rare, debilitating disease. However, it isn’t possible to be certain from this research alone whether the build up of TDP-43 protein is the reason why the nerve cells die. This study will no doubt stimulate more research into this disease, which currently has few treatments.

Where did the story come from?

Dr Christopher Shaw and colleagues from King’s College London, research centres and Universities in Australia, Italy and the UK carried out this research. The study was funded by The Wellcome Trust, the American ALS Association, the UK Motor Neurone Disease Association, the Medical Research Council, the Middlemass family, Jack Cigman, King’s College Hospital Charity, The Psychiatry Research Trust of the Institute of Psychiatry and the Motor Neurone Disease Research Institute of Australia (MNDRIA). It was published in the peer-reviewed scientific journal: Science .

What kind of scientific study was this?

Researchers identified the protein involved in the disease, then looked for mutations in the gene coding for the protein. In this case, researchers knew that the TDP-43 protein builds up in the motor nerves of people with ALS, and so they looked at the gene, called TARDBP , that codes for this protein.

The researchers examined the TARDBP gene in 154 people with ALS who had a history of the disease in their family to see if they could find any mutations (changes in the genetic code) within the gene. These people did not have mutations in any of five other genes already known to be associated with ALS.

Once the researchers identified a person with a mutation in the TARDBP gene they studied the genes of their family to see whether there was a link between this mutation and ALS. To look at how common the TARDBP gene mutations are, the researchers also looked for them in 200 British and 172 Australian Caucasians with sporadic ALS (that is, ALS that occurs in a person who does not have a family history of the disease). They also looked at the whole gene in 1,262 people from these countries who did not have ALS (controls).

The researchers then looked at how the mutations they found affected the function of the protein by introducing mutated or normal forms of the TARDBP gene into cells grown in the laboratory, and in chick embryos.

What were the results of the study?

The researchers identified one mutation in the TARDBP gene in a Caucasian family, and this mutation was predicted to alter the makeup of the TDP-43 protein. The same mutation was found in four other people in the same family with ALS, but not in nine unaffected family members. Genome-wide analysis within this family showed an association between the region of chromosome 1 where the TARDBP gene lies and ALS. No other regions showed a significant association.

Of the 372 Caucasians from Britain and Australia with ALS within the study, the researchers found two other people with ALS with mutations in this gene. Among the 1,262 people without ALS in the control group, they found one mutation in the TARDBP gene, but this was in a different region of the gene to where the mutations in people with ALS had been found.

When the researchers investigated the effects of the ALS mutations in the spinal cords of chick embryos they found that the embryos did not develop normally, and that more cells were dying than in embryos with the normal TARDBP gene.

What interpretations did the researchers draw from these results?

The researchers concluded that mutations in the TARDBP gene may be linked to ALS, but that these mutations are rare.

What does the NHS Knowledge Service make of this study?

This study identified mutations in the same region of the TARDBP gene in both familial and sporadic cases of ALS, and showed that mutations can have an effect on embryonic development. Together, these findings make it more likely that these mutations play a role in the development of the disease. Mutations in this gene were only found in three of the 526 people with ALS who were tested. Researchers also found a mutation in a different part of the gene in one person without ALS, and future research may or may not show that it affects the TDP-43 protein in the same way as the mutations thought to cause ALS.

This study reveals more about the complex genetic basis of ALS, and will stimulate further research into the biological processes behind the disease. Although these studies can be complex, they have the potential to bring treatments for these debilitating diseases closer.

Sir Muir Gray adds…

Better understanding of disease mechanism is always welcome, but does not necessarily lead to effective action.