Study Rationale:
Two proteins, PINK1 and Parkin, prevent cell death by breaking down damaged mitochondria, cell's energy generators. This process is known as mitophagy. Mutations in PINK1/Parkin genes -- genetic changes that render these proteins unable to perform their function -- cause Parkinson's disease (PD). Failure to remove damaged mitochondria from the cell can start or speed up the course of PD. Given the similarity of mechanisms of PD with genetic and unknown causes, we will search Parkinson's Progression Markers Initiative (PPMI) data for mitophagy-related cases of PD.
Hypothesis:
We will search genetic PPMI data for changes in the PINK1/Parkin genes. The experimental approach that we chose could help us understand if the genetic changes we find cause PD. We also aim to identify new genes involved in PD and new targets for future therapies as well as learn exactly how failure of mitophagy affects the course of PD.
Study Design:
We will analyze the complete sets of genetic information and other data from PPMI participants to identify those who have mitophagy-related disease. Their unique genetic features -- genes and their changes -- will be ranked by priority, and the changes with the highest priority will be further analyzed for their ability to disrupt mitophagy, induce PD and influence disease severity.
Impact on Diagnosis/Treatment of Parkinson's disease:
This study will clarify the role of the PINK1/Parkin genes and their changes in clinical course of PD, and identify new therapeutic targets and strategies.
Next Steps for Development:
This study will help to select the most suitable PPMI participants for clinical trials of therapies developed specifically for PD and related disorders caused by poor removal of damaged mitochondria.