Study Rationale:
Age is the single most significant risk factor for developing Parkinson’s disease (PD), but the mechanisms by which aging contributes to PD are not well understood. Within every cell there exists machinery and proteins (including heterochromatin) which forms the epigenome. The epigenome controls gene expression, and this control weakens with age, which may explain why cells begin to fail as we age. One reason for this age-related weakening is the erosion of heterochromatin. Recently, it has been shown that PD is associated with accelerated epigenetic aging and this may explain not only why people develop this condition, but also the different types, or heterogeneity, of PD.
Hypothesis:
The central hypothesis is that accelerated heterochromatin erosion in specific cell populations within the brain drives the onset and clinical expression of PD. We believe this mechanism may also help explain why patients present in different, heterogenous, ways.
Study Design:
Using new high-throughput molecular technologies, we will investigate the state of the epigenome in individual cells in postmortem brain samples from people with PD that we followed in life and from different age-matched control groups. We will study different brain regions that are differentially affected by PD, including areas that are severely affected and others that seem immune to the disease. These experiments will enable us to map epigenome aging in the PD brain and its relationship to the disease. We will then mechanistically investigate these findings by studying different types of aged human nerve cells grown in the lab and discover how we can prevent it from happening in PD.
Impact on Diagnosis/Treatment of Parkinson’s disease:
This project will identify how aging in PD affects heterochromatin erosion in different cells of the brain and the effect this has on their health and thus pathology. This knowledge will provide a new perspective on what goes wrong in PD and opens up for new treatment approaches.
Next Steps for Development:
Our project will generate an unprecedented, detailed map of epigenetic changes in the aging PD brain. This map will serve as a foundation for developing strategies to rejuvenate the epigenetic state especially in PD including developing novel genome editing approaches to achieve this.