Keeping motor neurones alive and well
Proteins that promote the survival of nerve cells may be the key to slowing motor-neurone disease, if we can learn which cells they affect and how they work. Background Motor neurones are the nerve cells that control the body's muscles. If some of them die, the corresponding muscles cannot function. This happens in patients suffering from motor-neurone diseases such as spinal muscular atrophy in children (the most frequent autosomal genetic disease after cystic fibrosis) and amyotrophic lateral sclerosis in adults (new cases are as frequent as spinal cord injury). These diseases are severely disabling and often fatal. Scientists have identified proteins called neurotrophic factors which help keep nerve cells alive. Some of these may have therapeutic potential, but so far clinical trials have been disappointing. One reason may be poor delivery of the factors to their target sites, but it is also possible that the treatments are not targetting the right motor neurones. It is important to know how and to which neurones different neurotrophic factors deliver their survival-promoting signals. This is the aim of an EU-funded project "Establishment and maintenance of muscle innervation: the role of neurotrophic factors". Description, impact and results In cases of motor-neurone disease, not all motor neurones are equally affected: weakness may begin in the facial muscles or may first affect the limbs, and some muscles are spared. Functionally, scientists distinguish different types of motor neurones: fast or slow, controlling muscle contraction or tension. These functional differences and diverse clinical patterns must reflect molecular differences between motor neurones, which the project participants aim to elucidate. One approach is to find specific markers of the neurones that control muscle tension. Selective labelling of these neurones has been achieved. A second approach is to study the specific receptors to which neurotrophic factors bind and through which they act. One fact has clearly emerged: different motor neurones bear different sets of receptors and respond to different neurotrophic factors. In mice, it has been possible to mutate certain receptors functionally and observe the resulting symptoms. Other achievements include the identification of new neurotrophic factors for motor neurones (hepatocyte growth factor, persephin) and the discovery of two new receptor sub-units. The teams have also learned much about how neurotrophic factors `tell' motor neurones to survive - if small molecules exerting the same effects as neurotrophic factors exist, they might be better therapeutic agents than the neurotrophic factors themselves. The project has yielded new methods for testing such molecules. Beyond the project itself, the knowledge gained and methods developed will be exploited by a new start-up company, TROPHOS, which will screen chemical libraries for small molecules potentially useful in treating motor-neurone disease. Working partnerships The project partners all share an interest in neurotrophic factors but their specialisations are complementary: motor-neurone biology (INSERM U.382 Marseille, France), neurotrophic factor receptors (EMBO, Heidelberg, Germany), factor-receptor interactions (Istituto di Biologia Molecolare, Pomezia, Italy), nerve-muscle junctions (University of Oslo, Norway), signalling by receptors (Universidad de Lleida, Spain), hind-brain motor neurones and neurotrophic factors (Karolinska Institute, Stockholm, Sweden), proprioceptive neurones (University of St Andrews, UK).