Research Areas

Medical Sciences Division Themes

• Neuroscience

• Musculoskeletal Science

• Genetics and Genomics

Group Members

• Dr Esther Becker, Postdoctoral Researcher
• Dr Emmanuelle Bitoun, Postdoctoral Researcher
• Dr Rebecca Fairclough, Postdoctoral Researcher
• Dr Aurelie Goyenvalle, Postdoctoral Researcher
• Dr Janet Kenyon, Postdoctoral Researcher
• Dr Peter Oliver, Postdoctoral Researcher
• Arran Babbs, Research Assistant
• Ben Edwards, Research Assistant
• Allyson Potter, Research Assistant
• David Powell, Research Assistant
• Sarah Squire, Research Assistant
• Vivienne Wilkins, Research Assistant
• Akshay Bareja, Graduate Student
• Alastair Crisp, Graduate Student
• Mattea Finelli, Graduate Student
• Justin Moore, Graduate Student
• Anna Dulneva, Graduate Student

Our research is focused on the understanding of muscle disease, movement and behavioural disorders.  We have developed various genetic models in order to understand disease pathogenesis as well as to develop effective treatments. Our studies range from the analysis of single gene defects such as Duchenne muscular dystrophy (DMD) to the use of genetic models which provide insights into the understanding of neurodegenerative diseases such as ataxia, as well as mental impairment and schizophrenia.

Current Research Programmes

MUSCULAR DYSTROPHY

Duchenne muscular dystrophy is the most common genetic form of muscular dystrophy affecting 1 in 3000 boys. Although the disease is known to be caused by the absence of the cytoskeletal protein, dystrophin, no effective treatment is yet available.  Our research programme is directed towards an understanding of the role of dystrophin through the analysis of related and associated proteins.  These studies in turn are providing insights into the pathogenesis of DMD and of other muscular dystrophies.  For example, we have shown that the dystrophin associated complex at the sarcolemma is linked to the intermediate filament protein desmin via the intermediate filament-like protein, syncoilin.  We are currently investigating the role of syncoilin in both skeletal and cardiac muscle as well as nerve.

 The dystrophin-associated protein complex

Therapy for DMD is a challenge since the protein is large and needs to be delivered to many muscle cells in the body for therapeutic effect.  We are taking a novel approach to treatment through the analysis of a protein closely related to dystrophin, called utrophin.  We have demonstrated that over expression of utrophin in the mdx animal model of the disease prevents the muscle pathology in both skeletal and cardiac muscle.  Our data suggest that up-regulation of utrophin might be an effective treatment.  One of the lead compounds developed with Summit plc is currently being taken to the clinic by BioMarin Pharmaceuticals and we are working on follow up compounds.

An additional promising strategy for DMD is the delivery of DNA vectors that cause the transcriptional machinery in muscle cells to miss out the mutated exons in dystrophin responsible for DMD; this method generates a smaller but functional protein that will prevent the disease occurring. Using antisense oligonucleotides into U7snRNA/AAV vectors, we have shown that this ‘exon skipping’ approach can successfully restore expression of the dystrophin gene in cellular and animal models of DMD.   The advantage of AAV based U7snRNA vectors is that they show more sustained expression than naked antisense oligonucleotides.  We are currently testing vectors that can skip multiple exons to cover many of the regions of the protein mutated in DMD patients simultaneously so that more patients can be treated using this approach.

MOTOR NEURON DISEASE

We are part of a Motor Neuron Disease Centre (director Dr Kevin Talbot). We are studying the function of the survival motor neuron (SMN) gene and its role in spinal muscular atrophy (SMA), a motor neuron disease which is leading cause of death in childhood.  We have various mammalian models where we can address the function of SMN.  In collaboration with Dr David Sattelle and Dr Ji-Long Liu in the MRC Unit, we are studying the function of SMN in the worm and the fly using genetic techniques such as siRNA and suppressor screening. 

NEUROGENERATIVE AND BEHAVIOURAL DISORDERS

We are investigating movement and neurodegenerative disorders through the characterisation of specific neurological mutants from the ENU mutagenesis programme at the MRC Mammalian Genetics Unit at Harwell.  For example, we have shown that the robotic mutant demonstrates loss of Purkinje cells in the cerebellum due to a mutation in the transcription factor Af4. We are currently investigating how Af4 causes this highly specific pattern of neurodegeneration by examining the expression profiles of RNA from laser-captured Purkinje cells.  Microarray analysis has revealed pathways where therapeutic intervention may be possible.  AF4 is closely related to LAF4 and FMR2 which when mutated results in learning and developmental difficulties in man. Initial studies of LAF4 shows that it is very important in the developing cortex.  The study of this gene family is allowing us to explore common pathways which when perturbed cause different disorders of the CNS.

Left: Calbindin immunostaining of wild-type (WT) robotic cerebellum sections showing the region-specific pattern of cell death. Right: Laser-capture microdissection of individual Purkinje cells before and after removal from a cerebellum tissue section.

We have recently characterised a second ataxic mutant named Moonwalker that shows adult-onset Purkinje cell death due a mutation in an ion channel, Trpc3. We have shown that the mutation influences the normal function of the channel causing an impairment in Purkinje cell development. Currently we are investigating the molecular pathways that link Trpc3 to neurodegeneration.

Slice culture of Purkinje cells showing stunted growth and expansion of axons from the moonwalker mutant.

Oxidative stress in the CNS is a feature of some of the most common neurodegenerative disorders such as Parkinson’s disease (PD), Huntington’s disease (HD) and ALS. We have recently shown that the gene mutated in the new Bella mutant occurs in a family of uncharacterized proteins that are part of the cell’s response to oxidative stress. The mice show ataxia and cell death in the cerebellum.  Current work is establishing the function of the causative gene using primary neuronal cell culture, protein interaction assays and transgenic mouse models. We are also looking at the expression of these genes in human neurodegenerative disease.

The blind-drunk mutant harbours a mutation in SNAP-25, a protein essential for normal exocytosis in neuronal cells. These mice display ataxia, but also a complex behavioural profile with aspects relevant to psychiatric diseases such as schizophrenia. Recently we have been investigating the influence of the environment on this behaviour. In addition, we are examining the sleep / wake (circadian) activity of these mice, as sleep disturbance is a common symptom of schizophrenia.

In silico modeling of the blind-drunk mutation (I67T) in the SNARE exocytosis complex containing SNAP-25

For an up-to-date list of PubMed publications, please click  here

Main Collaborations

Within Oxford University:

Dr Kieran Clarke, (Physiology Anatomy and Genetics) on cardiac function in skeletal muscle mutants

Dr Zoltan Molnar (Physiology, Anatomy and Genetics) on schizophrenia, cortical development and non-coding RNA in the CNS

Professor Chris Ponting (FGU) on the function of non-coding RNA in the CNS

Prof. Nick Rawlins (Experimental Psychology) on molecular basis of behaviour

Professor David Sattelle (MRC FGU) on worm models of SMA.

Dr Kevin Talbot (Physiology, Anatomy and Genetics/Clinical Neurology) on motor neuron disease

Dr Clive Wilson (Physiology, Anatomy and Genetics) on the role of human disease orthologues in Drosophila melanogaster

Dr Maike Glitsch (Physiology, Anatomy and Genetics) on the electrophysiology of Trp channels

Prof Russell Foster (Department of Opthalmology) on circadian analysis of synaptic mouse mutants

Sheena Lee (OXION) on microarray expression analysis and pathway modeling

External:

Professor Steve Brown and Dr Pat Nolan (MRC Mammalian Genetics Unit, Harwell, Oxon) on mouse neurological mutants

Dr Francesco Muntoni (Hammersmith Hospital, London) on muscular dystrophy

Funding Sources

Amyotrophic Sclerosis Association, USA

Association Francaise contre les Myopathies, France

Medical Research Council, UK

Muscular Dystrophy Campaign, UK

Muscular Dystrophy Asssociation USA

Parent Project UK

SMA Trust,UK

Jennifier Trust,UK