Loss of function mutations in the genes encoding PINK1 and Parkin results in early-onset forms of Parkinson's disease (EOPD). Both enzymes are functionally linked and together direct a neuroprotective mitochondrial quality control (mitoQC) ensuring elimination of damaged organelles from cells via the autophagy-lysosome system (i.e. mitophagy), which is lost in EOPD. Given the complexity of this pathway and the general missing heritability in EOPD, it is highly likely that additional genes regulating this pathway may also be found mutated in EOPD. The overarching goals of this project are to 1) identify high confidence genetic modifiers of the PINK1/Parkin pathway by a two-tiered functional screening (overlay of genome-wide siRNA and miRNA screens) in cells, 2) to identify the underlying genetic variation and characterize the EOPD genome (whole-genome-sequencing of patients), as well as 3) to determine the pathogenicity of these novel EOPD sequence variants in functional readout studies. Using this combined functional genetics approach we will determine the regulation of mitophagy as well as the genetic architecture of EOPD.