Study Rationale: Although loss-of-function mutations in the PINK1 and Parkin genes are known to cause early onset Parkinson’s disease (PD), the cellular and molecular mechanisms remain uncertain. We and others have previously found that PINK1 and Parkin mutations increase the amount of inflammatory molecules called cytokines in the brain and blood, which can cause neurodegeneration. However, the cellular source of these proinflammatory cytokines is unknown. Moreover, although rats bearing these mutations develop pronounced locomotor dysfunction, the root cause must be identified to develop and test interventions that could lead to better treatments for PD.
Hypothesis: We hypothesize that mutations that eliminate PINK1 and Parkin cause PD by increasing neuroinflammation in brain cells that may differ from the dopamine-producing neurons that degenerate in PD.
Study Design: In mice, we will disrupt PINK1 selectively in different, specific brain cell types to pinpoint the source of the proinflammatory cytokines that we hypothesize are the root cause of PD-related neurodegeneration. In rats, we will examine tissues before, during and after the onset of the locomotor dysfunction to better identify the root cause behind the neurodegeneration induced by PINK1 and Parkin deficiency.
Impact on Diagnosis/Treatment of Parkinson’s disease: By identifying the specific cell types and cell functions that are most altered by PD-linked mutations in PINK1 and Parkin, this study will facilitate the development and testing of PD therapeutics that are targeted to the most appropriate cells and the most promising functional pathways for modifying the course of PD.
Next Steps for Development: This study will facilitate future testing of novel drugs or other PD therapeutics for their ability to restore the normal function of the cells and pathways that are most responsible for causing PD-related neurodegeneration and for testing the extent to which this approach can slow or halt PD progression clinically.