Dr Anna Migdalska-Richards, Institute of Clinical Biosciences, College of Medicine and Health, University of Exeter
Prof Jonathan Mill, College of Medicine and Health, University of Exeter
Prof Nigel Williams, School of Medicine, Cardiff University
During this PhD, you will be one of the very first people to study the genome-wide epigenetics of Parkinson’s disease. You will determine the first-ever DNA methylation profile in distinct brain cell types of individuals with Parkinson’s. This will involve combining the exciting areas of epigenetics, genetics and bioinformatics. This work will lead to improved mechanistic understanding and suggest novel drug targets to treat this devastating condition.
Parkinson’s disease (PD) is the most common human motor disorder, affecting ten million people worldwide. With an increasingly ageing population, prevalence is predicted to double by 2030. Parkinson’s significantly contributes to the global burden of disease, costing the NHS alone more than £1 billion/year. Currently, there are no treatments that can cure or modify the disease, so development of new therapies that can slow, prevent or reverse PD progression are urgently required. Although some genetic components of Parkinson’s disease have been identified, much is still unknown about the aetiology. For example, the most common genetic risk factor (GBA1), which accounts for ~85% of all known genetic cases, shows incomplete penetrance, with only 30% of GBA1-mutation carriers developing the disease. Further, PD concordance rate between identical twins is only about 17%.
This indicates that non-DNA-sequence variation (i.e. epigenetics) plays a crucial role. In particular, recent work (including our own) shows that DNA methylation (the most well-studied epigenetic mark) is altered in the brains of people with Parkinson’s disease. It is now believed that future progress can only be made by understanding both the genetics and epigenetics of PD.
It is well-known that PD pathology differs both between brain regions and cell types. However, despite this, all previous studies of DNA methylation in PD brains have only analysed bulk brain tissue. This is a substantial drawback since results then include a mixture of cell types, each with their own epigenetic profile. This will mask the individual PD signatures from distinct cell types, and so hamper both mechanistic understanding and the search for novel drug treatments.
Supported by a recent £100k Wellcome Trust Seed Award, this project will directly address this problem by, for the first time, determining the role of DNA methylation in Parkinson’s disease separately in neurons, oligodendrocytes, and other glial cells. This has only recently become possible due to development of the method for separating cell-specific nuclei.
In addition, this project will (also for the first time) stratify individuals based on genetics. This will include both genome-wide SNP profiling and targeted gene sequencing, focussing on the GBA1 gene, but also including other PD risk genes such as SNCA, LRRK2, PRKN and PINK1. The hope is that this approach will lead to a step change in PD research, resulting in new mechanistic understanding and putative novel drug targets.
During this project, the student will learn a broad range of experimental and theoretical skills, including purification of neural nuclei, FACS sorting, DNA methylation profiling, genetic profiling and bioinformatics analyses. Although mainly based at the University of Exeter, six months will be spent investigating the genetic aspects of this project at the University of Cardiff in the group of Professor Nigel Williams.
Further, through collaboration with Dr Ryan Ames at the Living Systems Institute, the student will have the opportunity to develop basic computational network modelling skills in order to analyse genetic-epigenetic interactions. In addition, via collaboration with Professor David Collier, the student’s training will be further enhanced by regular visits to Eli Lilly for industrial experience, training and participation in seminars/courses. Finally, public involvement will play an important part of this PhD. This will build on existing links that we have recently developed with local Parkinson’s support groups, particularly those in Okehampton, Crediton and Exmouth. The student will participate in a number of public workshops, where they will be able to explain their work and interact directly with individuals affected by Parkinson’s disease.
To apply for this project, please complete the application form at https://cardiff.onlinesurveys.ac.uk/gw4-biomed-mrc-doctoral-training-partnership-student-appl
by 5pm Friday 25 November 2019.