In normal cells, Parkin protein senses damage of critical cellular organelles known as mitochondria and promotes recycling of their contents. Mitochondria are the energy generating centers of the cell, which has as a side effect the generation of highly reactive oxygen species, which accumulate and damage mitochondria. In cells with non-functional Parkin, we hypothesize that non-functional mitochondria accumulate, triggering premature cell death. The rate limiting step in moving forward to drug discovery is filling in the unknown molecular players in the processes of sensing mitochondrial injury and recruitment of Parkin to damaged mitochondria.
We suggest that there are as yet unidentified genes that regulate Parkin activity by influencing both its ability to sense mitochondrial damage and its ability to be held or retained on mitochondria once recruited there. To identify novel genes that regulate Parkin, we propose to use a comprehensive genetic screen in human cells using high-throughput robotic imaging. This ‘functional genomics’ technique involves monitoring the location of Parkin protein in cells with damaged mitochondria. Using a comprehensive genome-wide approach, we will then discover what genes are required for Parkin to move to mitochondria and thus to sense and respond to mitochondrial damage.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Given the central role of mitochondria in the etiology of both familial and sporadic forms of Parkinson’s disease, we contend that our screen for new genes that control Parkin function will yield important new mechanistic information about PD pathogenesis and provide novel therapeutic targets for future drug development.
We expect to identify genes that are necessary for Parkin recruitment to mitochondria, a major regulator of mitochondrial integrity. We expect to open up new avenues to address how Parkin regulates mitochondrial function, quality control and in turn, cell fate. In addition to furthering our mechanistic understanding of Parkin in mitochondrial homeostasis, novel genes (‘hits’) from this screen are potential new targets for the development of new therapeutics for PD. The application of our functional genomic technology to identify novel components that relay mitochondrial integrity information is anticipated to provide a framework with which one can begin to design an informed, directed approach to promote survival of neurons.