Alpha-synuclein is the primary component of Lewy Bodies and has been shown to spread in a prion-like manner in Parkinson’s Disease (PD). Despite being expressed throughout the brain, it is unclear why alpha-synuclein aggregation begins in substantia nigra dopamine neurons. One possibility is that the metabolism of dopamine itself may be involved in the pathogenesis of PD. Dopamine is first metabolized to DOPAL, a toxic intermediate which has been shown to contribute to neuronal cell death and alpha-synuclein aggregation. Here I test the “catechol-aldehyde” hypothesis of Parkinson’s Disease by manipulating the concentration of DOPAL in vivo by targeting enzymes involved in its the production and degradation. My findings so far demonstrate that genetic manipulations that decrease the concentration of DOPAL reduce the propagation of alpha-synuclein preformed fibrils (aSyn-PFF) and slow the loss of dopamine neurons in a mouse aSyn-PFF model. In ongoing experiments, I am testing a pharmacological approach to reduce the concentration of DOPAL and am examining whether this will be useful in treating prodromal Parkinson’s Disease.