The epigenetics of Parkinson's disease: searching for novel drug targets

Background to Parkinson's disease
Parkinson's disease (PD) is the most common human motor disorder, affecting one-in-twenty individuals by age 85. It is currently estimated that seven to ten million people worldwide have PD. With an increasingly ageing population, this condition will become more and more common, and prevalence is predicted to double by 2030. As a consequence, PD significantly contributes to the global burden of disease, costing the NHS alone more than £1 billion/year. There is still remarkably little known about the causes of Parkinson's, and there are currently no treatments that can cure or modify the disease. The few treatments that do exist only alleviate symptoms temporarily and become substantially less effective after only a few years. Therefore, development of new therapies that can slow, prevent or even reverse PD progression are urgently required.

Genetics and epigenetics
Although some genetic components of Parkinson's 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 PD cases, shows incomplete penetrance, with only 30% of GBA1-mutation carriers developing the disease (PD-GBA1). Further, the concordance rate for Parkinson's between identical twins is only about 17%. This indicates that non-DNA-sequence variation, such as epigenetics, plays a crucial role in Parkinson's. In particular, recent work (including my own preliminary data), 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 Parkinson's.

The current problem
It is well-known that PD pathology differs both between brain regions and cell types. In particular, in addition to neurons (whose role in PD via alpha-synuclein accumulation and dopaminergic neuron loss is well-established), multiple studies have shown that oligodendrocytes and other types of glial cells are also involved. However, despite this, all previous studies of DNA methylation in Parkinson's 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 signatures of Parkinson's from distinct cell types, and so hamper both mechanistic understanding and the search for novel drug treatments.

The proposed project
This project will directly address this problem by, for the first time, determining the role of DNA methylation profile in individual cell types of the prefrontal cortex in both people with Parkinson's disease and matched controls. In particular, this will include separate analysis of 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.