Study Rationale: Mutations in the PINK1 and Parkin genes cause early-onset Parkinson’s disease (PD). In rats with similar mutations in PINK1 and Parkin, we observed pronounced degeneration of nerve fibers called axons, which coincided with significant locomotor impairments. Our analyses of mice bearing PD-linked mutations in PINK1 revealed that PINK1 is particularly important for maintaining the function of microglia, the brain’s resident immune cells. Now, we will determine how PINK1 deficiency affects microglial cells in the brain, particularly their propensity to cause neuroinflammation, and we will assess how deficiency for PINK1 and Parkin affects the integrity of axons in the brain’s neurons.
Hypothesis: We hypothesize that mutations in PINK1 and Parkin cause PD by decreasing the integrity of neuronal axons and by increasing the propensity of microglia to induce neuroinflammation within the brain.
Study Design: To test our hypotheses, we will analyze neuroinflammation in the brains of mice in which PINK1 is mutated only within microglia and not in other brain cells. We will also analyze the integrity of axons in the brains of rats with mutations in both PINK1 and Parkin. Lastly, we will analyze samples of rat blood and cerebrospinal fluid to identify markers of neurodegeneration linked to mutations in PINK1 and Parkin.
Impact on Diagnosis/Treatment of Parkinson’s disease: An increased understanding of the cell types and cell functions that are most altered by PD-linked mutations in PINK1 and Parkin will facilitate the development and testing of therapeutics that are targeted to the most appropriate cells and to the most promising functional pathways for modifying the course of PD.
Next Steps for Development: This study will facilitate development of quantitative tests for PD-related neurodegeneration and the testing of novel drugs or other PD therapeutics for their ability to restore the normal function of microglial cells within the brain and to protect neurons against the degeneration that underlies the clinical symptoms of PD.