Dr Guy Bewick
Dr Gareth Miles
Preventing motor neuronal loss is a major goal in MND research. However, enhancing function in surviving motor neurones is also crucial. Before a cure is found, this will maintain patient quality of life for longer. After a cure is found, it would restore the lost functions that prompt patients to present for treatment.
Transforming growth factor-β2 (TGFβ2) is a protein found under motor nerve terminal contacts in muscle fibres. We recently discovered it has a major role in enhancing nerve-muscle signalling (Fong et al., 2010. PNAS 107:13515). This finding led us to propose this is how TGFβ2 restores lost motor function in a commonly studied model of motor neurone disease – a striking effect that is so far unique to TGFβ2.
Here we propose to test this hypothesis directly by asking if TGFβ2 reverses deficits in nerve-muscle signalling in this MND model. We will also test whether it regulates inputs onto motor neurones in the spinal cord or affects early cell death signalling. Finally, since injections of precursor TGFβ (‘latent’ TGFβ) are better tolerated in humans, we will test ‘latent’ TGFβ2 for similar beneficial effects at nerve-muscle contacts.
Overall, this study is a major step in assessing the therapeutic potential of targeting TGFβ2-based signalling to improve motor function, and hence quality of life, in motor neurone disease.