GL Brown Prize Lecture: Tackling the pathophysiology of motor neuron disease (MND): a translational neuroscience approach

Motor neuron disease (MND) is one of the 3 commonest adult onset neurodegenerative disorders with a prevalence of approximately 6-8/100,000. The clinical features are caused by injury and cell death usually of both upper motor neurons in the brain and lower motor neuron groups in the brainstem and spinal cord. Death in most patients results from neuromuscular respiratory failure. The rapidity of disease progression in many cases causes MND to be regarded as one of the most feared diseases in medicine. The heterogeneity and complexity of MND has poses a challenge for neuroprotective therapy development. This lecture will cover 5 areas of topical interest in relation to this neurodegenerative condition.

1. An introduction to the intricate and fascinating properties of the human motor system and what goes wrong to cause the clinical and pathological features of MND.

2. A discussion on current thinking in relation to disease pathogenesis ie why motor neurons die. New generation genetic sequencing techologies have enable rapid progress in unravelling genetic causes of motor neuron degeneration. Insights into disease pathophysiology arising from study of experimental models of MND will be discussed, including our ability now to reprogamme skin cells do create a human model of MND in the laboratory. Pathophysiological changes at cellular and in vivo in rodent models and human patients will be highlighted.

3. New scientific approaches that can be applied to the problem of MND will be considered. These include laser capture microdissection to isolate motor neurons and study their properties in great detail. In addition, the repertoire of cellular gene and protein expression of motor neurons in health and disease states, can be studied using transcriptomic and proteomic approaches respectively. The other new approach is to investigate the contribution of the “neighbourhood” cells in the nervous system eg astrocytes in the initiation and/or propagation of motor neuron injury.

4. The next section of this presentation will consider whether we are winning in terms of the translation of recent scientific research into benefits for patients who develop MND. Progress in neuroprotective therapy development, including gene therapy approaches and in improving life expectancy and quality of life by advances in symptom management will be considered.

5. The final section will consider how the relationships between scientific researchers and patients, the public and society are changing and the positive value emerging from this two-way relationship. Two illustrative examples include the creation of SITraN and the development of a new, recently marketed device for neuromuscular disorders.