Study Rationale: Parkinson’s disease (PD) has long been associated with mitochondrial dysfunction. Perturbation of these subcellular structures can lead to the release of reactive oxygen species (ROS), which triggers inflammation and cell death. Thus, approaches that boost the removal of damaged mitochondria, a process called mitophagy, have the potential to prevent neuroinflammation and neurodegeneration. In cells, mitophagy can be triggered by a process that tags mitochondrial proteins with a marker called ubiquitin. We will determine whether inhibiting USP8, an enzyme that removes ubiquitin from mitochondrial proteins, can enhance neuroprotection by stimulating mitophagy in human neurons and in a preclinical PD model.
Hypothesis: We hypothesize that inhibiting the ubiquitin-removing enzyme USP8 in human neurons will offer therapeutic benefits, potentially preventing neuroinflammation and neuronal cell death.
Study Design: To evaluate USP8 as a therapeutic target, we will examine the effects of highly specific and potent small-molecule inhibitors of USP8. We will treat neurons derived from people with PD with these specific inhibitors, and measure mitochondrial function and mitophagy. At the same time, we will also employ a newly generated preclinical mouse model to determine whether inhibiting USP8 under physiological and PD-associated pathological conditions has neuroprotective effects.
Impact on Diagnosis/Treatment of Parkinson’s disease: If successful, this study will identify a novel target, USP8, for which inhibition is protective in preclinical PD models and in neurons derived from people with PD.
Next Steps for Development: If successful, the work will show that existing small-molecule inhibitors of USP8, which are already used in cancer therapy, can also be effective as therapeutic avenues for PD.