Awarded to Professor Kay Davies and Dr Kevin Talbot, Oxford University, 2004
In 2004 The Jennifer Trust began funding a research project at Oxford University that focussed on the molecular analysis of families with spinal muscular atrophy. As this project draws to a close, the principle investigators, Professor Kay Davies and Dr Kevin Talbot, have provided the following report.
There area number of different forms of SMA which, although caused by mutations in different genes, cause very similar patterns of weakness. Whether these genes interact in the s ame pathways or have entirely separate functions is important for several reasons. The relationship between various 'motor neuron survival' genes will help give us a complete picture of how motor neurons are maintained as healthy cells and why this goes wrong in diseases. In addition, by connecting different forms of SMA we may be able to use common therapeutic approaches across a number of diseases. The co mmon form of SMA is due to loss of protein called SMN, which is produced from a gene called SMN1. A number of different strategies are being used around the world to increase the amount of SMN protein in motor neurons including delivery by gene therapy using viruses and screening for drugs that naturally increase the amount of SMN being produced from the very similar copy gene called SMN2. Another approach is to identify if targeting other pathways that we know cause motor neuron degeneration can help protect these cells when SMN levels are low.
- In the last five years four new genes that lead to forms of SMA have been identified. We have completed screening of these genes in a large number of DNA samples from patients from the UK and abroad. This revealed that of the 120 SMA cases screened, we were only able to identify mutations in 7 cases. This means that there are a number of other SMA causing genes awaiting discovery.
- One such gene is called 'small heat shock protein B1'. Its function is thought to be the protection of cells under conditions of stress. We have studied what happens when a mutated form of this gene is put into nerve cells growing in the laboratory and shown that the effect of mutations is to disrupt the mechanism for transporting protein up and down the very long process of the nerve cell that is important for its connection to muscle.
- In order to see if increasing the amount of HSPB1 protein protects motor neurons under stress and could prevent the progression of SMA we have created mice which produce excess amounts of HSPB1. We are currently crossing these with mice which develop SMA due to deficiency of SMN to see if it can offer protection. If so, HSPB1 would then have potential as a drug to treat SMA.
Another gene we have screened is called GARS. Mutations in this gene cause a form of SMA which tends to affect the hands and feet and to progress only slowly and not in general to affect lifespan. We have studied the effect of these mutations by making crystals of the GARS protein and analysing how the mutations affect its function. The importance of GARS is that, like SMN, it is a gene present in every cell in the body but which only affects motor neurons when mutated. |
