The role of dopamine in Huntington’s disease

In the Huntington’s disease (HD) brain, the pathology affects the dopaminergic system Interestingly, the most commonly used treatment for the motor symptoms of HD blocks dopamine receptors suggesting a decrease in dopamine signaling may be beneficial in this disease. However, to date, very little attention has been paid on the effect of these drugs in animal models of HD. This research aims to investigate the dopaminergic system in animal models of HD.

The role of the immune system in Parkinson’s disease and its associated dementia

Parkinson’s disease progresses at different speeds in different individuals, with some individuals having a rapid disease course and developing memory problems and a dementia within a few years of diagnosis, and others having a more benign course with relatively little disability for many years. Dementia in PD occurs when the pathological changes (including the deposits of alpha synuclein) spread from the deep movement centres of the brain out to the outer cortex, but the factors driving the rate of this progression of pathology are not well understood. The immune system may play a critical role, and would be an attractive target for disease modifying therapy. Such therapy is much needed given the devastating impact of dementia on the patient and their family, and the lack of effective therapies for this aspect of the disease currently available.

This programme of work is supported by generous funding from the following charities and organisations: Academy of Medical Sciences, Rosetrees Trust, Addenbrooke’s Charitable Trust, Wellcome Trust, Stevenage Biosciences Catalyst.

Activated-microglial-cells

Activated microglial cells (indicating inflammation) in a post mortem sample from a Parkinson’s disease brain

Gaucher’s disease and Parkinson’s disease

This work centres on a recently described genetic predisposition to developing Parkinson’s disease that relates to the gene causing Gauchers disease. The work is based in the lab on creating neurons from skin cells collected from skin biopsies. These neuronal models are a unique research tool as they represent person specific cells. The aim is to use these neurons to model the neurons affected in Parkinson’s disease. The technique is very new so we are currently optimising the experiments and for this we are working with Dr. Malin Parmar’s group from Lund University who are experts in this technique.

This work is supported by the Rosetrees Trust and ARUK.

Gauchers-disease-skin-biopsies

Using stem cell-based approaches to model Parkinson’s disease dementia in human brain cells

Human induced pluripotent stem cells (iPSCs) can be generated from adult cells such as skin cells. Using the right culture conditions, these iPSCs can then be differentiated into functional nerve cells.

In a collaborative project with the Livesey group we use cerebral cortex neurons to model neurodegeneration and dementia associated with Parkinson’s disease in a human-based cell culture system. This stem cell-based approach allows us to study aspects of disease initiation and progression in human brain cells as it was not feasible previously. We are particular interested in the role of the protein alpha-synuclein that forms the abnormal aggregates that are a hallmark of PD.

Human-induced-pluripotent-stem-cells

Neurodegenerative animal models: characterisation and treatment strategies

This area of research examines rodent models of Huntington’s (HD) and Parkinson’s disease (PD) to better understand the disease process and for trialling new treatment strategies, in hopes to translate these findings to clinical trials in human patients. One main area of interest is in the non-motor ‘behavioural’ features of the disease (such as cognitive impairment, apathy and impulsivity) as this has a significant impact on quality of life. I am currently examining the effect of established and novel neuroprotective drugs in genetic HD mouse models. Both strategies have already been shown to have therapeutic benefit in models of PD. I am also working within the group to develop and characterise a novel rat model of PD which may give us a greater understanding of the disease process and a better model for trialling new treatments.

Comparison-of-brain-sections-from-HD-model-mice

Dopamine neuronal development and PD

We are studying the development, maintenance and functioning of subsets of midbrain dopamine neurons that are lost in PD. This involves looking at the developing midbrain in rodent and human midbrains as well as the pattern of dopamine cell loss in post mortem tissue for patients dying from PD.

  • Figure 1: Human Midbrain: a section of human adult midbrain stained with an antibody for tyrosine hydroxylase, labelling the dopamine neurons.

  • Figure 2: Dopamine Neuron: a high magnification image presenting human midbrain dopamine neurons (red), some of which are expressing calbindin (green).

  • Figure 3: Laser Capture: illustrating the isolation of subsets of dopamine neurons from a section of human adult midbrain, using laser capture microscopy.

Disease modelling

We are trying to better model the clinical progression of Huntington’s disease (HD). By working with engineers, we have shown that the trajectory of HD progression can be modelled and predicted for individual patients. With data from clinical assessments over the past 2 years, it is possible to predict how disease would progress over the next 2 years with a 90% accuracy. The aim is to minimise the need to use placebo control in clinical trials.We are now working to refine and improve the model and prediction accuracy. This work is mainly supported by the Rosetrees/Butterfield Trust.

Disease-trajectory

The above figure shows the disease trajectory of individual patients seen in our clinic over the past 10 years. Different patients can exhibit very different patterns of disease progression.

 

Cell transplantation

We are working to improve the outcome of cell transplantation therapy in Parkinson’s disease (PD). 90% of the grafted cells are lost in the first two weeks post-transplantation due to the hostile environment in the adult central nervous system. We are now seeking to develop better ways to protect these cells by grafting them with supporting scaffoldsThis work is mainly supported by the UK Regenerative Medicine Platform (UKRMP).

scar-formation-surrounding-the-grafted-cells

The above figure shows massive scar formation (green) surrounding the grafted cells between 4 to 16 weeks post-transplantation. Such scar formation can potentially interfere graft-host interaction and compromise the survival and function of the transplant.

Tau and HD

This research focuses on understanding the possible role of tau protein in the pathogenesis of Huntington’s disease (HD), which is still unclear. We have recently shown that tau pathology is a prominent feature in HD and we now plan to further explore and extend the characterization of tau pathology in other regions of the HD brains (Background) Pathological tau aggregates in Huntington’s disease brains. (Foreground left) George Huntington (1850-1916) who first described the disease bearing his name in a report ‘On Chorea’ published in The Medical and Surgical Reporter of Philadelphia on April 13, 1872.

tau pathology