This grant builds upon the research from a prior grant: Functional Genomic Screening to Identify Novel Regulators of Parkin
Promising Outcomes of Original Grant:
The protein Parkin is thought to be required for the maintenance of healthy mitochondria, critical subcellular organelles that govern cellular energy production and cell survival. In the original Rapid Response Grant, we were trying to identify accessory factors required for the protein Parkin to carry out its normal function. Using a comprehensive, genome-wide imaging approach, we successfully identified eight new such candidates. We also validated a lead hit, ATPIF1, as a factor required for Parkin to work properly.
Objectives for Supplemental Investigation:
The work that we will now do stems directly from the outcome of our year of funding. Specifically, we will continue to elucidate the mechanism of action of ATPIF1 and how it is required for Parkin activity and its involvement in maintenance of the health and function of mitochondria. We will also focus on two other top candidates from our initial screen and attempt to confirm their roles in Parkin function. As our screening work to date has required the use of non-neuronal cell lines, we will now also evaluate the roles of ATPIF1 and other validated leads in mitochondrial function in neuronal cell cultures.
Importance of This Research for the Development of a New PD Therapy:
We have identified new factors that are required for Parkin to promote repair of mitochondria, which we believe has opened 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, any novel factors we identify can be a new target for the development of novel therapeutics for PD.