Study Rationale: In Parkinson’s disease, loss of nigral dopaminergic neurons leads to motor symptoms. PINK1 and PRKN are both proteins involved in mitochondrial quality control, which when carrying loss-of-function mutations cause familial forms of Parkinson’s disease. Uncovering which outcome measures should be used to evaluate PINK1 and PRKN activities in vivo will be integral to our long-term goal of identifying markers that could be useful for clinical trials and establishing mammalian models for testing PINK1/PRKN activators.
Hypothesis: We hypothesize taking a candidate approach to analyze predicted PINK1/PRKN-dependent outcome measures and employing strategies known to induce mitochondrial stress and enhance mitophagy will be instrumental in designing a panel of markers useful for evaluating PINK1 and PRKN activities in vivo.
Study Design: We will utilize banked tissues and samples from the WT and Polg mice from the PINK1 and PRKN knockout cohorts of our previous project for assessment of additional readouts (i.e., mitochondrial DNA (mtDNA) copy number and mutation load, inflammation markers, PRKN protein levels and activation status, and compensation through other parallel mitophagy pathways such as BNIP3/NIX) to correlate other measures of damage with pS65-Ub levels we already collected from almost ~ 1,000 tissue samples. Beyond the banked tissues, to enhance mitophagy, mice will be treated with a USP30 inhibitor, VB-08, provided by Vincere Biosciences, and to induce mitochondrial stress, mice will be treated with rotenone.
Impact on Diagnosis/Treatment of Parkinson’s disease:These studies will be instrumental for uncovering which outcome measure(s) should be used to evaluate PINK1 and PRKN activities in vivo, important for identifying markers that could be useful for clinical trials and establishing preclinical models for testing PINK1/PRKN activators.
Next Steps for Development: The outcome measures identified through these studies will serve as potential therapeutic targets for future studies.