The role of the immune system in Parkinson’s disease
Our cohort studies, following large groups of individuals with Parkinson’s disease over time, have shown us that the disease progresses at different speeds in different individuals. Whilst some have a rapid disease course and may develop memory problems and even dementia within a few years of diagnosis, others have a much more benign course with relatively little motor or cognitive disability for many years. We propose that the immune response to the disease is an important factor which contributes to this variability in the disease course. Caroline Williams-Gray is leading a programme of studies investigating this theory. These include:
- Clinico-pathological studies, characterising inflammation in post mortem brains of individuals with Parkinson’s, and investigating the relationship with the rate of clinical and cognitive progression during life;
- PET neuroimaging studies using the ligand PK-11195 to measure inflammation within the brain in early Parkinson’s disease;
- Investigating inflammatory cytokines and other immune markers in blood samples from our large Parkinson’s cohorts, and assessing their value in predicting and tracking disease progression;
- Immunophenotyping studies which characterise immune cell subtypes in blood and cerebrospinal fluid samples;
- Assessing the role of Toll like receptors in mediating the immune response in Parkinson’s using ‘in vitro’ and ‘in vivo’ models.
Ultimately, all of this work is helping us to better understand the immune changes that occur in both the brain and the peripheral blood in Parkinson’s. Furthermore, it is providing critical evidence that these changes are relevant in driving disease progression – with important implications for new treatment strategies targeting the immune system to slow the progression of Parkinson’s.
This programme of work has received funding from the Academy of Medical Sciences, the Rosetrees Trust, Addenbrooke’s Charitable Trust, the Wellcome Trust, Stevenage Biosciences Catalyst, the Evelyn Trust, the Medical Research Council, Michael J Fox Foundation.
Activated microglial (inflammatory) cells in a post mortem Parkinson’s disease brain.
NET-PDD (the role of NEuroinflammation and Tau Aggregation in PD Dementia) – is a longitudinal PET neuroimaging study led by Caroline Williams-Gray and co-ordinated by Antonina Kouli.
The primary goal of the study is to better understand the earliest changes in the brain that lead to memory problems and dementia in PD. Our previous research has contributed to the theory that two processes – tau aggregation, and inflammation within the brain – might play a critical early role. The NET-PDD study is investigating this theory by comparing markers of these processes in two groups of newly-diagnosed patients: a group at high dementia risk, and a group at low dementia risk; as well as healthy volunteers of similar age for comparison, recruited from the NIHR Cambridge Bioresource. Inflammation and tau deposits are measured using PET neuroimaging, as well as in the cerebrospinal fluid and the blood. Participants are assessed with PET scans, lumbar punctures and blood tests as well as detailed clinical and cognitive assessments at baseline and again at 3 years, to assess how measures of inflammation and tau accumulation change over time, and how they relate to the development of memory problems and dementia. Clinical follow-up will continue for up to 10 years.
Establishing whether inflammation and tau deposition are important early events in Parkinson’s disease dementia will bring us much closer to developing new treatments to prevent or slow the onset of this complication of the disease, which has such devastating consequences for patients and their families. We also aim to determine which combination of the imaging, CSF and blood-based markers we are studying is likely to be most useful for tracking progression of dementia and the effect of treatments on this over time – which will be critical for future clinical trials of these treatments.
This study is supported by funding from the Evelyn Trust and the Medical Research Council.
PET scan showing uptake of the ligand [18F]AV1451, indicating widespread cortical accumulation of tau in a patient with Parkinson’s disease.
Modelling PD in vitro using induced neurons (iNs)
One area that we are particularly interested in, is the identification of new potential treatments for Parkinson’s disease. Our work in this field involves testing treatments in laboratory models of PD. One approach that we are using is to generate “induced neurons” from patients. Using this novel technique we are able to take skin cells from patients, and convert them directly into neurons, the cells that are affected in PD. Unlike some similar cell-based models, this does not involve a stem-cell stage, which means that the induced neurons retain the age-signature of the patient. This is important, given that PD is predominantly a disease of ageing. We have found that if we treat these cells with fibrils of α-synuclein (the protein that becomes abnormal in PD), they develop collections of this protein, and problems with the energy production system in the cells, similarly to what is thought to happen in patients. We are using this system to test specific treatments, to see if they are able to reduce the problems that we see in the induced neurons, with a view to prioritising them for clinical trials.
This study is supported by funding from the Cure Parkinson’s Trust and the National Institute for Health Research (NIHR) pilot scheme
Representative pictures of iNs showing the presence of abnormal protein aggregates before (left) and after (right) exposure to pathological α-synuclein. Colour indicates cell nucleus (DAPI: blue), neuronal marker (βIII tubulin: red), and protein aggregates (pFTAA: green).
Modelling PD in vivo using systemically delivered alpha-synuclein fibrils
Although motor dysfunction in PD is related to the progressive loss of midbrain dopamine neurons, the presence of pathological “Lewy-bodies” are not confined to this area and can be found in selective regions across the brain. We have recently found that a non-selective, systemic delivery of α-synuclein fibrils is able to generate highly specific pathological features in discrete regions, similar to those observed in early stage PD patients. In addition, functional declines in the gastrointestinal tract and in the olfactory system are observed preceding the onset of motor impairments, again similar to those seen in PD patients without a family history of the disease. We are now in the process of better characterising this novel model of PD, with an aim to aid therapeutic development by testing putative drugs identified in the aforementioned iNs platform. We are also trying to understand the molecular basis of the selective neuronal vulnerability, which is observed in idiopathic PD as well as in our models.
This study is supported by funding from the Medical Research Council (MRC)
Representative pictures showing the presence of α-synuclein pathology in selective brain regions at 6 months after a non-selective, periphery delivery. Colour indicates cell nucleus (DAPI: blue), phosphorylated α-synuclein (Ser129, red), and protein aggregates (pFTAA: green).
Glucocerebrosidase and Parkinson’s disease
Genetic mutations in the glucocerebrosidase gene (GBA1) represent the most common genetic risk factor for Parkinson’s identified to date. One of our PhD students, Tom Stoker, has been working specifically on Parkinson’s disease associated with mutations in the GBA1 gene. This work has involved taking skin cells from patients, and reprogramming these cells in the laboratory so that they turn into nerve cells (induced neurons). Through this approach, we are able to study the problems that occur in cells from people with GBA1-Parkinson’s, in order to find out more about how GBA-1 contributes to the disease. We can also test the ability of new drugs to correct the abnormalities in these cells. By screening a number of different drugs in this way, we hope to be able to identify the most promising candidates for future clinical trials in patients.
Induced neurons produced in the lab by reprogramming of skin cells taken from a patient with Parkinson’s.
The Pluripotent Stem Cell and Engineered Cells (PSEC) is a research hub under the UK Regenerative Medicine Platform (UKRMP), an interdisciplinary research program, established to address key translational challenges of regenerative medicine. The program under the directorship of Prof. Roger Barker is aimed at addressing key outstanding hurdles to translate human Pluripotent Stem Cell (hPSC) based cellular therapies into standard clinical practice and enabling their commercial development. We are generating new tools, protocols and resources
- To determine what constitutes a genetic risk in an hPSC-derived cell product in terms of patient safety;
- To optimise the production of hPSC-derived cell products to reduce genetic risks while allowing for the manufacturing of economically viable treatments;
- To develop assays determining the immunogenicity of hPSC-derived cell products using in vitro and in vivo models
- To develop “smarter” PSC-based cell therapies using genetic engineering to reduce the need for immunosuppression.
This project is funded by Medical Research Council.
Mature dopaminergic neurons made from human embryonic stem cells. The neurons were grown in a dish show expression of tyrosine hydroxylase (green), an enzyme that converts L-tyrosine to L-DOPA, a precursor of dopamine. b-tubulin (red) is a pan-neuronal marker.
Gut dysfunction in Parkinson’s disease
Marta Camacho is leading a study investigating gut problems in the earliest stages of Parkinson’s and how they are linked to immune activation, and disease progression.
Our long term cohort studies suggest that early constipation may be associated with more rapid disease progression. We would now like to test the theory that abnormal gut function in PD leads to changes in the bacterial constituents of the gut (the microbiome) and increased inflammation, which in turn activates the immune system and accelerates PD progression. To test this, we will assess gut function, immune activation and movement and cognitive (memory/thinking) changes over time in 3 groups: 1) patients with early PD, 2) people at high risk of developing PD, to assess whether gut problems exist in the advance of PD, and 3) healthy controls matched by age and gender. Participants will be assessed every year over a period of 3 years with a new questionnaire to measure gut problems, blood tests, and stool samples as well as detailed clinical and cognitive assessments. Further clinical follow-up will continue for up to 10 years.
Establishing whether gut problems and associated inflammation are important early events in Parkinson’s disease will help us to better understand how the disease works. If this study has positive findings, it may pave the way for developing therapies targeting gut function, in order to slow the onset of complications such as memory and balance problems, which are considered to be amongst the most devastating complications of Parkinson’s by patients and their families.
This study is supported by funding from the Evelyn Trust and the Dementia and Neurodegeneration Pilot Study Funding Scheme 2019-2020.