Dissecting the role of the adaptive immunity in the Parkinson's phenotypes using deep data

Background: Parkinson's disease (PD) is a devastating neurodegenerative disease that affects 160 people per 100,000 in the United Kingdom. Because of population growth and an increasingly aged population, the estimated prevalence and incidence of PD in the UK is expected to increase. There is currently no cure for PD (or any other neurodegenerative disease).

The cost of illness escalates as a patient's PD progresses, placing an economic burden on the healthcare system and society and impacting the lives of patients and their families. PD is associated with a loss of neurons expressing a chemical called dopamine. Multiple studies added increasing evidence that PD is also an auto-immune disease.

These studies show that patients shortly after their diagnosis have many immune memory T cells in their blood that respond specifically to a protein called alpha-synuclein. This protein, the hallmark of PD, accumulates inside brain's neurons of PD patients. Memory T cells are immune cells that remember the specific molecular features of past infections or auto-immune reactions.

However, all these studies don't establish whether autoimmunity is a prime cause rather than a secondary reaction. In addition, these studies focused on T cells in the blood and did not bring direct evidence that these cells target neurons in the brains of people with Parkinson's. In this research program, we will sequence T cells and their cellular environment in the post-mortem brain tissue collected in PD patients at different stages to discover whether this is the case.

Therapies targeting the adaptive immune system have been successful in many disorders e.g. cancer/auto-immune disease/infectious disease. These therapeutic strategies could be quickly repurposed in PD if we fully understand the role of T cells in PD (Objective 1).

In any case, even if the T cell reactivity was secondary, these observations suggest that monitoring these T cells might identify Parkinson's individuals pre-symptomatically, enabling earlier interventions to preserve neurons while at-risk populations. To date, the presence of rapid eye movement (REM) sleep behaviour disorder (RBD), an abnormal condition where people physically act out dreams, is the best early indicator for PD, with 80% of patients progressing to PD.

We have collected and banked blood samples from RBD patients before they have been diagnosed with any neurodegenerative condition. Analysing the blood of RBD patients could retrospectively identify changes in the immune system that reflect conversion to PD. Here, we will sequence blood cells from RBD individuals with the aim of identifying changes in specific cells of the immune system.

These indicators ("biomarkers") offer a better chance of early diagnosis and targeted, timely treatment of patients, improving quality of life, and generating a rich dataset for future research (Objective 2).

One final obstacle to establishing the causality of T cells in PD is that the clinical presentations of each patient vary so greatly, suggesting the existence of different subtypes and influences. Medical imaging studies of PD patients and studies of biopsies and gut and brain tissue from biobanks recently pointed out that in some patients, the brain is affected before (brain-first) the peripheral nervous system (body-first).

The existence of the body-first subtype is supported by the fact that some PD patients at an earlier stage present gastrointestinal symptoms e.g. constipation. We hypothesise that T-cells may play distinct roles in body-first vs brain-first PD aetiologies. By integrating different T cell signature specific to PD with different biomedical data, we will determine in which PD clinical subtype T cells play a prominent role.

The development of therapies that prevent disease onset or slow down the disease progression are of limited value until we can identify who would benefit from them and when to deliver treatment (Objective 3).