Parkinson’s disease is characterized by aggregation of α-synuclein and mitochondrial dysfunction, both of which can lead to oxidative stress through the excess production of reactive oxygen species (ROS). Nrf2, the master regulator of the antioxidant response, regulates the transcription of hundreds of cytoprotective genes that have roles in removing ROS from the cell. However, endogenous activation of the antioxidant response is insufficient in providing protection from Parkinson’s. DHA has been demonstrated to provide neuroprotection from models of neurodegenerative disease, including PD. However, the specific mechanisms underlying these responses remain to be elucidated. To investigate this, wildtype and transgenic fat-1 mouse brains were analyzed for changes in gene expression associated with endogenously high omega-3 fatty acids. In addition, immortalized and primary cell cultures were assessed following α-synuclein preformed fibril (PFF) and DHA treatment. PFFs and DHA have additive effects on activation of the antioxidant response, rescuing the cell from oxidative stress.