Grant: Project Grant

Damaged mitochondria in neurons are a frequent cause of early-onset Parkinson's disease. Parkin protects neurons by tagging damaged mitochondria for degradation via a recycling system termed autophagy. We previously obtained 3D images of parkin and showed it is normally inactive but becomes active in the presence of damaged mitochondria. The goal of this project is to study small molecules that activate parkin, particularly variants with mutations that prevent its normal activation. In a recent publication, we identified a molecule that acts as a protein glue and allows the activation of parkin variants that cause Parkinson's disease. We will build on this discovery to identify new molecules that bind and control parkin. To test these, we will develop a system in fruit flies for studying parkin function. Historically, fruit flies are an important organism for biological research and provided the first evidence, over 20 years ago, that parkin is essential for healthy mitochondria. By identifying the mechanisms by which parkin is activated and labels mitochondria for recycling, our studies will aid the development of drugs to treat Parkinson's disease.