Department of Neurodegenerative Disease
UCL Institute of Neurology, Queen Square
Professor of Neurogenetics
Department of Neuromuscular Diseases
UCL Queen Square Institute of Neurology
We are interested in learning more of the genetic basis of two disorders that involve neurodegeneration in humans: motor neuron diseases and Down syndrome and the resulting susceptibility to Alzheimer's disease. We work with the mouse as a genetic model for aspects of human neurodegenerative disease.
Motor neuron diseases (MNDs) are common and incurable, and arise when the motor neurons that extend from the brain into the spinal cord and out to the muscles, degenerate and die. Spinal muscular atrophy, one form of MND is the biggest single genetic killer of children, and amyotrophic lateral sclerosis (ALS) is an adult form of MND that arises in mid-life. Although single genes are known that cause MNDs, it is not clear how the mutant genes exert their effects or what other genes can modify the pathways involved. Many different cellular systems are affected, including RNA metabolism, and we collaborate with a number of groups, including those of Dr Pietro Fratta, Adrian Isaacs, and Professors Linda Greensmith and Giampietro Schiavo at UCL to analyse the mouse models we create for perturbations in RNA and other changes.
We are also working with mouse models of Down syndrome; all this research is in collaboration with Professor Victor Tybulewicz of the Francis Crick Institute. Down syndrome is the most common known genetic form of cognitive disability and the most common genetic factor for susceptibility to Alzheimer disease (AD). Down syndrome commonly results in the histopathology of AD in the brain, in the mid-30s (although not necessarily behavioural changes). Some form of neurodegeneration may be taking place, and, interestingly, there are also changes in axonal transport in Down syndrome. We are characterizing our mouse models in order to look specifically at the relationship to AD pathology and electrophysiological changes (in collaboration with Professor Matthew Walker and Dr Stephanie Schorge, UCL) and behavioural changes, and then to try to work out which genes are responsible for changes we find, as such genes are likely to be important for neurodegeneration in the general population.
Doctor of Philosophy
|Imperial College of Science, Technology and Medicine|
|University of Oxford|
I have an undergraduate degree from St Anne’s College, University of Oxford, in Physiological Sciences which I took between 1978 – 1981. In 1983 I started a PhD in mouse molecular genetics, the microdissection of the mouse X chromosome at St Mary’s Hospital Medical School (Imperial College). My primary supervisor was Professor Steve Brown and I undertook a considerable part of the PhD under the supervision of Dr Mary Lyon at MRC Harwell. This was a technically demanding project involving the dissection of individual chromosomes and cloning DNA fragments into plasmids, in nanolitre volumes. I completed the PhD in 1986 and in 1987 started my postdoctoral work with Professor David Page at the Whitehead Institute, MIT. I started working on a project to find the human male sex determining factor and then moved onto a project to identify genes involved in Turner syndrome. This turned was one of the early human positional cloning projects.. In 1990 I returned to UK on a Royal Society Research Fellowship to start my independent lab at Imperial College, studying the effects of aneuploidy. In 1991 Victor Tybulewicz (at MRC NIMR) and I gained funding from the Wellcome Trust to start a long-term project to create a new ‘humanised’ mouse model of Down syndrome, which led to the research project we now pursue jointly to use mouse molecular genetics to find the individual dosage sensitive genes giving rise to aspects of Down syndrome. In parallel my lab has also created and analysed a series of mouse models with motor neuron degeneration, trying to shed light on why motor neurons die in the disease amyotrophic lateral sclerosis. These two research themes come together in an interest in mouse models in neurodegeneration.
In 2007 I was elected to become a Fellow of the Academy of Medical Sciences, in 2009 I became a Member of EMBO, and in 2010 I became a Fellow of the Royal Society of Biology. I am a Wellcome Trust Senior Investigator, held jointly with Victor Tybulewicz.