The Department of Clinical Neuroscience is one of the leading academic units for clinical neuroscience in the UK. Research in the Department is focused on neurodegenerative disorders, epilepsy, health services research, brain injury and stroke, and builds on collaborations with the Departments of Neuroscience, Neuroimaging and Psychology. Research programmes within the Department include: Motor Neurone Disease (MND) and related disorders - The Department hosts the Kings MND Care and Research Centre, one of the world’s leading centres for MND research and the development of new treatments; Movement disorders (particularly atypical Parkinsonian syndromes such as PSP and MSA); Epileptology, with particular interest in developing new electrophysiological, neuroimaging and cognitive approaches to understanding epilepsy; Neurogenetics, particularly linkage studies and complex genetics in MND, Parkinsonian disorders and epilepsy; Acute brain injury.
Activities and Interests
Headache
Guy's & St Thomas's Hospital Charity fund the Neurology & General Practice Unit for Service Delivery and Evaluation of innovation in Headache Services. Six GPs with Special Interest in Headache have been trained. Intermediate Care Clinics have been set up in Southwark and Lambeth and an evaluation published in the BJGP. Patients seen by the GP with Special Interest Service were more satisfied than patients who saw hospital-based general neurologists. The PCT was charged less for the GPwSI service than for hospital care. Further work is in progress to develop a CBT intervention for Migraine.
Prior work funded by the MRC set the stage for this by examining the reasons for referral of patients with headache to specialists. It was found that GPs referred only 2% of consulters for primary headache to neurologists. These patients reported the same level of headache severity and disability as patients managed in primary care. Referred patients expressed more fear and anxiety about their headache symptoms. GPs reported that patient pressure was important in the referral decision, and their wish for a brain scan.
A new study designed to describe the prevalence of PFO and their association with migraine, and trial clopidogrel in the prevention of migraine has begun in collaboration with John Chambers (PI), and funded by the Dunhill Trust.
Fatigue
A Wellcome Trust grant funded the third complex intervention trial by this unit for patients with chronic fatigue in primary care. This three-arm RCT of Graded Exercise, Counselling and Usual Care plus a booklet on CBT has been completed, with results presented at meetings, and papers submitted for publication.
Epilepsy
Prior work has included trial of nurse interventions for people with new and chronic epilepsy. An NIHR SDO grant funds the unit for a study titled: Can nurse-led rehabilitation for epilepsy patients prevent non-planned admissions? A comparison of cost and effectiveness of service models at two centres. This is currently recruiting patients at King's College Hospital and Guy's & St Thomas' Hospitals.
Epilepsy Bereaved is funding an epidemiological study of causes of mortality in epilepsy, using the General Practice Research Database, in collaboration with Martin Gulliford.
In collaboration with Brian Hurwitz, the Unit is hosting Maria Vaccarella, who is funded by a Marie Curie Fellowship, to explore the relationship between epilepsy in the arts and the experience of epilepsy care.
Teaching Activities
Leone Ridsdale is Director of Neurology Undergraduate Clinical Teaching, and Chair of Clinical Teaching in Year 3 for the Neurology-Opthalmology-Psychiatry Rotation. In the past, medical graduates have reported lack of competence and confidence in neurology, amounting to 'neurophobia'. KCL students do 12 a week rotation in clinical neurology, linked with psychiatry teaching. This has been evaluated, and KCL students report as much confidence in their neurology knowledge and skills, as in other Year 3 subjects. Students rated neurology as top, tied with cardiology, for interest and as the subject in which they would like to specialize (Ridsdale L, Massey R, Clark L. (2007) Preventing 'neurophobia' in medical students, and so future doctors. Practical Neurology 7:116-123).
Nuclear receptor signalling
Cellular effects of retinoic acid (RA) are mediated by binding to nuclear receptors - the retinoic acid receptors (RARs) and retinoid X receptors (RXRs). There are three subtypes of each receptor, alpha, beta and gamma, and multiple isoforms of each subtype due to alternative splicing and differential promoter usage. RARs mediate gene expression by forming heterodimers with RXRs, whereas RXRs can mediate gene expression either as homodimers or by forming heterodimers with orphan receptors, which are also members of the nuclear receptor. The RAR/RXR heterodimers regulate transcription by binding to retinoic acid response elements (RAREs) in the upstream regions of target genes. Because the RAR genes contain RAREs, one notable effect of RA is its ability to induce the expression of the RARs themselves, thus stimulating various RA signalling pathways.
RARbeta2 signalling and neurite regeneration
We have shown that the RARbeta2 receptor induces neurite regeneration in vitro in both embryonic and adult neurons. In the adult spinal cord little or no expression of RARbeta2 can be detected, however when this tissue is transduced with RARbeta2 using lentivirus vectors neurite outgrowth occurs.
By microarray analysis we have identified a number of genes involved in neurite regeneration, which are regulated by RARbeta2.
RARalpha signalling and neuronal survival
By generating retinoid deficient rats we have shown that RARalpha as opposed to other RAR receptors is required for the survival of motoneurons, Purkinje neurons and cerebral cortex neurons the same receptor deficit is found in human pathology samples of spontaneous cases of motoneuron disease and Alzheimer’s disease (AD). By using both in vitro and in vivo assays a number of target genes known to be involved in AD have been identified which are regulated by RARalpha signalling. Current work involves manipulating the retinoid pathway in mouse models of neurodegeneration and assaying for target genes and behavioural analysis including open field, novel object recognition and T maze.
RAR signalling and stem/progenitor cell differentiation
We have identified specific roles of RARbeta and alpha signalling in neural progenitor cell (NPC) differentiation. This will allow the transplantation of stem cells with a defined lineage into the injured nervous system or the stimulation of endogenous progenitor cells in the injured CNS both of which may lead to functional repair.
Screening for novel retinoids
Retinoids are small molecules which have been shown to cross the blood brain barrier, and therefore have therapeutic potential for the treatment of CNS disorders. However, to date very few retinoids with drug like properties have been developed. We have set up screening assays for both binding (IC50) and potency (EC50) of retinoids at the RARs from which we can identify specific receptor agonists. These will be used in models of CNS injury described above.
The focus of work in my research group is on finding new approaches for the improved treatment of Parkinson's disease. Current strategies under investigation including targeting metabotropic glutamate receptors and replenishing depleted levelos of neurotrophic factors. It is hoped such strategies will help combat the progressive neurodegenertion that underlies this disease.
Parkinson Disease
Parkinson’s disease is a debilitating movement disorder that results from degeneration of dopamine-containing neurones in the nigrostriatal pathway. The resultant loss of striatal dopamine sets up downstream changes in firing within the basal ganglia motor loop that are manifest clinically as deficits in movement. Current treatments like L-DOPA, which replenish lost dopaminergic transmission, are initially effective at reversing the motor symptoms. However, these drugs do little to halt the relentless degeneration of dopaminergic neurones and the increasing doses of drug needed to counter ever-worsening symptoms bring about disabling side-effects such as dyskinesia. For this reason, alternative treatments that offer protection against the degeneration or do not evoke dyskinesia are eagerly awaited.
Metabotropic Glutamate Receptors
Excess glutamate transmission from an overactive subthalamic nucleus which innervates the substantia nigra controbutes not only to symptom generation, but is also one of many factors thought to contribute to the progressive nigral cell death. G-protein coupled group III metabotropic glutamate (mGlu) receptors that signal through Gi/Go are implicated in the negative regulation of glutamate release. Using in situ hybridisation and immunohistochemistry we have demonstrated expression of these receptors in the substantia nigra; electron microscopy studies of others have shown this localisation to be upon presynaptic glutamatergic terminals. If functional, activation of these receptors should reduce glutamate release in the substantia nigra and thereby provide a means not only of correcting the motor symptoms, but also of potentially offering much-needed neuroprotection. Our in vitro brain slice work has confirmed that at least two of the group III mGlu receptors (mGlu4 and mGlu7) have the capacity to reduce glutamate release in the substantia nigra, an effect we have since demonstrated in vivo for this class of receptor, using microdialysis. Activation of mGlu4 and mGlu7 receptors also reversed symptoms in rodent models of Parkinson’s disease. Of great promise, these targets also show considerable neuroprotective potential, being able not only to protect the neurones from degenerating, but also preserving motor function in rodent models of the disease. We are currently identifying which of the group III mGlu receptors holds the greatest neuroprotective potential and hope to follow the targeting of this receptor over a longer time frame to check on potential dyskinetic side-effects, for example. We also wish to explore in more detail the cellular and molecular mechanisms behind these beneficial effects.
Growth Factors and Neuro-repair
We have also started to examine the potential of biologicals, specifically fibroblast growth factor-20 (FGF-20). A number of growth factors appear to malfunction in Parkinson’s disease and FGF-20 in particular has genetic links with the disease which may result in a hostile environment for cells to survive in. Work carried out in our group so far has shown that replacement of this endogenous protective factor is an effective way of providing protection against toxin-mediated cell death both in dopaminergic cells in culture and in rodent models of Parkinson’s disease. It is not yet known how these beneficial effects are brought about – whether by direct actions on the dopainergic neurones themselves, which do express the relevant FGFR1 receptors (see Figure 1) or, as is the case with related factors (e,g. FGF2) via increasing the synthesis and release of other growth factors from glial cells. We hope our future studies will shed light on these mechanisms and inform us how best to effect protection with these agents.
Around 60% neurones have already degenerated when Parkinson’s disease signs first appear. In the adult brain, residual neurones have limited capacity for optimal rewiring and compensation because of certain molecules within the extracellular matrix of damaged sites that inhibit collateral sprouting and plasticity. In future studies we hope to find ways of countering these inhibitory molecules to encourage plasticity and rewiring of the brain in Parkinson’s disease.
The development of an undifferentiated cell into a neuron is a process that is fundamental to the formation of sensory tissues. In many tissues neurogenesis is preceded by a period of proliferation before cells exit the cell cycle and differentiate. Our goal is to understand the mechanisms by which developing tissues coordinate proliferation and neuronal differentiation.
We use the Drosophila eye to study the signals which control neurogenesis. Prior to photoreceptor differentiation an extensive proliferative phase generates a large pool of undifferentiated cells, which are then specified sequentially through reiterative use of the Notch and EGF receptor pathways. Neurogenesis in the Drosophila eye occurs in a spatio-temporal manner making it particularly well suited for studying temporal controls during differentiation.
Insulin receptor signalling and neurogenesis
We have shown that the conserved insulin receptor (InR)/Tor pathway plays a key role in controlling the timing of neuronal differentiation in Drosophila (Bateman and McNeill 2004, Cell 119, p.87-96). By using mutants in various components of the InR/Tor pathway, we showed that activation of this pathway causes precocious differentiation of neurons. Conversely, inhibition of InR/Tor signalling significantly delays neurogenesis. Correct timing of neuronal differentiation is essential for tissue pattern formation and consequently mutations in components of InR/Tor signalling cause pattern defects in the adult. One of the aims of our research is to determine the molecular mechanism by which InR/Tor signalling regulates the timing of neuronal differentiation in Drosophila.
Neurogenesis and disease
We are also interested in diseases in which Inr/Tor signalling plays a role. One such disease is Tuberous Sclerosis Complex (TSC). TSC affects 1 in 6000 live births and is caused by mutations in one of two genes (TSC1 or TSC2). The pathology of TSC is typified by the formation of benign tumours in the brain, kidneys and other organs, beginning in early childhood. One of the most debilitating manifestations among patients with TSC is the high prevalence and severity of epilepsy, with patients suffering from up to hundreds of seizures per day. TSC1/2 are core components of the InR/Tor pathway and we have shown that loss of TSC1 causes precocious neuronal differentiation in Drosophila. The demonstration that TSC1 controls the timing of neuronal differentiation and hence neuronal patterning in Drosophila is intriguing, since abnormal neuronal development and migration are a major part of the neuropathology of TSC.
Regulation of neuronal membrane trafficking by activity and pathology – a systemic approach
In order to fulfil their function, neurons must constantly readjust their functional properties in response to the activity of the system. A crucial element of this readjustment is dynamic regulation of surface expression of neurotransmitter receptors, ion channels and other membrane proteins. Through regulation of trafficking at (or near) the synapse, neurons achieve tight control over their most fundamental properties – synaptic transmission and intrinsic excitability. While much research has been focusing on activity-regulated surface expression of particular proteins, the comprehensive picture of activity-dependent regulation of neuronal membrane trafficking is lacking and the mechanisms underlying it are poorly understood. I propose to undertake a systemic characterization of the activity-dependent regulation of neuronal surfaceome (i.e. proteins expressed at the surface of the neuron) in the context of Alzheimer’s disease, using affinity purification, proteomics and subsequent characterization by imaging and biochemistry
Applicants should possess a minimum of an upper second class honours degree from a UK university or the overseas equivalent. Applicants whose qualifications have been gained outside the UK will be checked by the Health Schools Admissions Centre to establish equivalency with these standards before an offer is sent and applicants will need to demonstrate at interview that their background and experience, general education and scolarship are appropriate. All applicants need to possess an adequate level of English competence.
Available studentships are advertised at: http://www.kcl.ac.uk/iop/research/pgr/phdstudentships/index.aspx