Parkinson's disease (PD) is a debilitating motor and cognitive neurodegenerative disorder for which there is no cure. Currently, there is no clear understanding of what causes PD, although age, genetic susceptibility, and environment are all implicated. Aging itself is the number one risk factor for PD; ultimately, it will be the study of ll three factors together in appropriate models that will generate the most translatable discoveries vital for progression toward therapies. The nematode C. elegans is a simple model organism with a short lifespan that is both genetically and environmentally tractable, thus, its use greatly facilitates the study of the multi-factorial risks for PD. Mitochondrial dysfunction and oxidative stress are prominent pathological features in PD. Environmental exposure to the heavy metal manganese is a leading risk factor for developing PD and is known to cause toxicity by specifically targeting mitochondria. We find that we can recapitulate manganese-induced mitochondrial dysfunction in C. elegans. In addition, we find that young worms with mutations in parkin (which causes familial, early-onset PD) do not exhibit enhanced toxicity to manganese compared with wildtype, despite displaying increased expression of the iron/manganese transporters, SMF-1/-3. However, we have found that aged worms with parkin mutations display selective vulnerability to manganese, indicating that age-dependent changes contribute to toxicity in parkin mutants. We hypothesize that parkin mutants have age-dependent alterations in manganese transport, leading to elevated manganese levels and increased susceptibility to manganese toxicity. In support of this, we have found that aging and activation of pro-aging pathways lead to accumulation of manganese in animals, which suggests that manganese transport may naturally become altered with age. Moreover, parkin mutants show diminished activation of the mitochondrial unfolded protein response (UPR) following manganese exposure, which may lead to further accumulation of damaged mitochondria. We further hypothesize that impaired mitochondrial stress responses exacerbate vulnerability to manganese in aged parkin mutants. We propose to characterize age-dependent changes in manganese homeostasis and determine the genetic pathways that regulate sensitivity to manganese in aged parkin mutants. Finally, we will validate our results in a cellular model of PD. If we produce compelling data, these findings will begin to dissociate the complex, synergistic interactions among genes, environment, and aging that lead to disease, which could have significant therapeutic implications for age-related diseases. PUBLIC HEALTH RELEVANCE: Neurodegenerative diseases such as Parkinson's disease (PD) are a large class of debilitating motor and cognitive disorders. There is currently no clear understanding of what causes PD, although age, genetic susceptibility, and environment are all implicated. We propose to use C. elegans to study the complex interplay among PD risk factors, which will be validated in cellular models, and which has the potential to open new avenues for therapeutic interventions.