Study Rationale: Recent studies have discovered metabolism to be altered in Parkinson’s disease with cells changing their bioenergetic pathways and accumulating metabolite markers. Every cell in our body and brain is unique and it is important to study them as such, contrary to previous research that has analyzed all cells together as a mixture. Here we propose to provide exactly this missing information with the recently developed technology of single-cell metabolomics. We aim to identify similarities and differences in metabolic markers between patients and between individual cells from each patient. Together this detailed novel information will lay a foundation to find metabolic pathways that are affected in disease that may be targeted for therapeutics.
Hypothesis: We hypothesize that PD causes significant alterations in cell lipids and metabolites and that some of these alterations are also observed in prodromal cases and therefore may be useful as biomarkers of early disease.
Study Design: We will use cutting-edge technologies, pioneered by our team, which have not previously been applied to Parkinson’s disease. We will differentiate cells from the PPMI cohort of PD patients into neurons and glia – key cell types in PD - and will interrogate them using these technologies. We will obtain profiles of hundreds of metabolites and lipids from single cells and apply modern data analysis methods to identify differences within cell populations from individual patients and between different patients. The study will pinpoint prominent changes within the neurons that degenerate and how these are impacted by other cell types within the brain.
Impact on Diagnosis/Treatment of Parkinson’s disease: Our data will provide a metabolic signature for each cell from Parkinson’s patients, prodromal cases (people with early signs of disease) and controls that will be used to understand the metabolic pathways affected in each cell. By identifying these differences we may identify biomarkers for diagnosis or pathways that could be targeted for potential treatments.
Next Steps for Development: Biomarkers will be validated in mouse models of PD and in patient tissue. Drugs targeting potential pathways will be tested in cell and small preclinical models.