Project 457472

Affecting more than 10 million people worldwide, Parkinson's disease (PD) is characterized by a slow progressive loss of a subset of nerve cells in the brain called dopaminergic neurons. More than 10 years prior to clinical diagnosis, PD patients often already manifest subtle impairments, such as constipation. In addition, intestinal infections are also commonly reported among PD patients. Our group has data suggesting this causes dysfunctional immune responses potentially underlying the pathophysiology of the disease. Notably, we discovered that the disruption of a protein associated with PD, called PINK1, in mice following gut infection results in the immune system attacking dopaminergic neurons that are presenting self-peptides (known as autoimmunity), leading to PD-like symptoms. The spatial and temporal information of the cascade of autoimmunity remains unaddressed, as well as the immune mechanisms instigating neuronal attack along the gut-immune-brain axis. To determine precisely where, when and how autoimmunity occurs, we will employ state-of-the-art mapping of activated immune cells and assess the repertoire of immunogenic self-peptides at single cell resolution in relevant nervous and immune tissues during the course of disease. We will then mimic the interaction between neurons and immune cells in a dish by adding effector immune cells, known as T cells, with gut neurons from Pink1-deficient mice and neurons derived from inducible pluripotent human stem cells lacking Pink1, to ultimately assess the cause-effect relationship leading to neuronal death. In summary, our study will provide a comprehensive picture of autoimmunity contributing to PD pathogenesis. More importantly, the use of single cell technologies in our research will offer a unique advantage in studying a multifaceted disease, such as PD, and may address its heterogeneous manifestation in patients.