PROJECT SUMMARY/ABSTRACT Parkinson disease (PD) of both sporadic and genetic etiologies is associated with mitochondrial dysfunction. In particular, the PARK genes PINK1 and Parkin, which are known to cause autosomal recessive early-onset PD, have been implicated in the selective degradation of mitochondria by the lysosome-mediated degradation pathway macroautophagy (MA), also known as mitophagy. Given that PINK1/Parkin-dependent mitophagy was mechanistically characterized in invertebrate and mammalian cell-based systems, the precise role of these genes in regulating mitochondrial quality control in the mammalian brain has remained elusive, with constitutive loss of PINK1 or Parkin failing to robustly recapitulate key features of PD or show defective mitochondrial handling in the rodent brain. Establishing a link between human genetics data and the mechanistic studies in lower-order models is essential to understand the pathogenic nature of these genes and their contribution to mitochondrial quality control and PD. Using a combination of mouse genetics, optical fluorescent monitoring of mitophagy, protein biochemistry, neuropathology, and behavior, this proposal aims to build upon exciting preliminary data indicating that the inducible loss of Parkin expression in the adult mouse leads to levodopa-responsive defects in motor coordination and movement, and determine if the global loss of Parkin leads to a dopaminergic (DAergic) neuron- selective neurodegeneration reminiscent of PD. Aim 1 will determine if inducible loss of Parkin in the adult animal leads to a DAergic neuron-specific neurodegeneration and resulting PD-like neuropathology and behavior, whereas Aim 2 will use a newly created mitophagy reporter mouse to determine if mitochondrial turnover leads to the observed deficits. Aim 3 will build on initial observations suggesting that compensation in basal MA upon constitutive Parkin loss masks the necessity for Parkin for mitochondrial turnover and the maintenance of central nervous system health. Together, these studies will elucidate mechanisms of mitochondrial quality control in the mammalian brain and provide key insight into the roles of Parkin and mitophagy in the pathogenesis of PD.