Study Rationale: Before Parkinson's disease (PD) manifests its characteristic symptoms, the pathological process has been underway for years. Although the initial trigger remains uncertain, we have found that the proteins associated with PD significantly impact the immune system, suggesting that PD might be an autoimmune disease. In our experiments in preclinical PD models, we observe that T cells, which are normally responsible for fighting infections and cancer, begin attacking the brain's dopamine-producing neurons. These neurons are crucial for movement, and their destruction leads to the classic symptoms of PD.
Hypothesis: We hypothesize that PD is initiated by inherited or age-related defects in the immune system whereby infections drive production of autoimmune T cells that can lie dormant for years before they ultimately attack dopamine neurons in the brain, causing motor symptoms.
Study Design: Using human immune cells that carry PD-related mutations, we will map the precise steps at which these mutations interfere with immune signaling. Second, we will use gut organoid cultures to determine the very earliest changes in immune cell activation after infection in PD models. Third, we will determine how autoimmune T-cells become activated in the brain to kill dopamine neurons. Lastly, we will examine changes in immune signaling in blood cells from individuals at higher risk of developing PD and identify the specific protein fragments that engage the expansion of autoimmune T cells in patient-derived PD cell lines.
Impact on Diagnosis/Treatment of Parkinson’s disease: If successful, our study will allow us to identify key stages where drug therapies could be developed to act both early (outside the brain) and late (in the brain). Importantly, our tools can be developed to stratify patient engagement and monitor drug efficacy in trials.
Next Steps for Development: This research could pave the way for early treatments targeting the immune system, potentially preventing PD. The identification of a common set of protein fragments that drive selection of PD-related autoimmune T cells will allow us to screen individuals at very early, prodromal stages of disease.