Motor neuron diseases are a diverse group of neurodegenerative diseases presenting as a variable combination of weakness, muscle wasting and spasticity leading to progressive disability and dependence and, in the majority of cases, premature death from respiratory failure. 

Amyotrophic lateral sclerosis (ALS), often referred to simply as ‘motor neuron disease’ (MND) in the UK, is a malignantly progressive form of neurodegeneration characterised by the pathological hallmark of insoluble intraneuronal protein aggregates which stain positive for ubiquitin.  We have a poor understanding of the basic pathogenesis, including how ageing triggers the disease.  Even in familial cases the pathogenic mutation is tolerated by motor neurons for decades, implying age-dependent disease triggers are critical.  Analysis of high-expressing transgenic mouse models of SOD1-related ALS has not so far led to effective therapies.

Spinal Muscular Atrophy is a pure lower motor neuron disease, which in its most common form is a leading cause of disability in childhood.  Autosomal recessive SMA is caused by inactivating mutations in the SMN gene but the molecular basis of motor neuron specificity is poorly understood.

My research focuses on understanding the molecular and cellular basis of motor neuron specificity in neurodegenerative disease using mouse, fly and cellular models, with the ultimate aim of identifying therapeutic targets for treating patients in my motor neuron disorders clinic. 

Current Research Programme

• Assembly of a large DNA bank from patients with different forms of motor neuron disorder (spinal muscular atrophies, sporadic and familial amyotrophic lateral sclerosis) has allowed screening for mutations in novel genes that have emerged in recent years as causes of motor neuron degeneration. We have identified novel mutations in the genes for small heat shock proteins, the gene for  glycyl tRNA synthetase and others. 
• Functional work on small heat shock protein mutations  We have performed extensive transfection experiments on primary neuronal cells in culture and neuronal cell lines and demonstrated that mutant hsp 27 disrupts the key components of anterograde and retrograde axonal transport.
• GARS mutations have been analysed biochemically and structurally and in cell culture.  We are developing specific models to understand why mutations in such a ubiquitously expressed ‘housekeeping’ gene might lead to a specific neurodegenerative disease.
• Genetic and clinical characterisation of novel forms of lower motor neuron degeneration.  We have identified a large four-generation family lower motor neuron disease and, though linkage analysis, identified a novel. Candidate gene sequencing is ongoing.
• In partnership with Prof. Kay Davies we have developed models of SMN-related SMA with which to understand the process of cell death.
• In ALS we are  performing neuropathological studies on the brain and spinal cord using tissue donated by patients from the clinic.

Ataxias are a diverse group of neurological conditions in which the cerebellum degenerates leading to impaired motor coordination.  Patients develop slurred speech, difficulty in walking and in fine motor skills.  As with MND there are currently no treatments.  We are screening UK patients for mutations in ataxia genes and working with Prof. Davies’ group to develop models of ataxia.

Further information:

Motor Neurone Disease and Amyotropic Lateral Sclerosis: http://www.mndassociation.org  and http://www.alsa.org/ 

Spinal Muscular Atrophy: http://www.jtsma.org.uk or http://www.fsma.org

Ataxias: http://www.ataxia.org.uk/ 

Department of Clinical Neurology website: http://www.clneuro.ox.ac.uk/index.php?p=mnd

Kevin Talbot