Research at the Duty Lab
New Treatments for Parkinson's Disease
The Duty Lab research group focuses on finding new approaches for the improved treatment of Parkinson's disease. Current strategies under investigation including targeting metabotropic glutamate receptors and replenishing depleted levels of neurotrophic factors. It is hoped such strategies will help combat the progressive neurodegeneration that underlies this disease.
Parkinson’s disease is a debilitating movement disorder that results from degeneration of dopamine-containing neurones in the substantia nigra. 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. People with Parkinson’s also display a number of non-motor symptoms. One of these is pain, about which we know very little. Consequently, there is a need to discover what underlies pain in Parkinson’s so that we may better treat this symptom.
Metabotropic Glutamate Receptors
Excess glutamate release from an overactive subthalamic nucleus - which innervates the substantia nigra - contributes 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. Our focus in terms of neuroprotection has centred on targeting the mGlu4 receptor. We have shown that direct infusion of drugs that positively modulate activation of mGlu4 can preserve dopaminergic neurones and motor behaviour in a rat model of Parkinson’s disease. We are now examining whether systemic delivery of drugs targeting this receptor can also bring about such relief. The mGlu4 receptors is an exciting target because activation of this has been shown to alleviate other symptoms e.g. pain and anxiety, which might prove to be beneficial in tackling some of the non-motor signs of Parkinson’s disease. We also wish to explore the anti-dyskinetic potential of targeting mGlu4 and discover more about the cellular and molecular mechanisms behind these beneficial effects.
Growth Factors and Neuro-repair
We are also interested in the potential of growth factorsto provide neuroprotection and repair in Parkinson’s disease. A number of growth factors appear to malfunction in Parkinson’s disease. Fibroblast growth factor 20 (FGF20), for example, has genetic links with the disease which may result in a hostile environment for cells to survive in. Work carried out in our group 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 dopaminergic neurones themselves, which do express the relevant FGFR1 receptors 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.
Growth factors are very large proteins that do not gain access to the brain so require direct delivery there. This is not always practical and as an alternative we have been exploring ways in which we can boost the brains own supply of FGF20 through the use of drug repositioning. We have used algorithms designed, by our colleague Dr Gareth Williams, to scrutinise databases of transcriptional profiles of thousands of FDA-approved drugs. In doing so, we identified just less than twenty which switched on the gene encoding FGF20. We confirmed that many of these drugs increase FGF20 protein expression in cells and went on to show that four could elevate FGF20 levels in the brain regions affected in Parkinson’s. We are currently exploring how effective the best two of these drugs are at protecting dopamine neurones in our animal models of Parkinson’s. If successful, this work could identify a drug already known to be safe for use in people that boosts FGF20 and offers a more accessible treatment than direct infusion of the growth factor itself. We hope to use this targeted repurposing strategy in future projects.
Pain in Parkinson’s disease
As noted above, pain is one of the non-motor symptoms in Parkinson’s disease that affects over 60% patients and is poorly treated at present. There is still lost we don’t understand about the causes of pain in Parkinson’s disease. In collaboration with clinical (Professor K Ray Chaudhuri) and non-clinical (Professor Marzia Malcangio) colleagues, my team is trying to unravel the ways in which pain in Parkinson’s is bought about. We are especially interested in the role that neuroinflammation plays as well as how abnormal activity in the descending inhibitory pathways might contribute. These studies are at a relatively early stage, but already we have found some exciting pointers that we hope will help us better understand pain in Parkinson’s and eventually find better, more specific treatments to tackle this non-motor symptom.
Finlay CJ, Duty S, Vernon AC (2014). Brain morphometry and the neurobiology of levodopa-induced dyskinesias: current knowledge and future potential for translational pre-clinical neuroimaging studies. Frontiers in Neurology. June 2014 | Volume 5 | Article 95