Despite this ambiguity, approaches that may indiscriminately reduce α-syn in the central nervous system represent an active area of research as an approach for treating PD (e.g., AFFiRiS PD01, Prothena/Roche PRX002). In this Hypothesis and Theory article, we discuss evidence from rodent and non-human primate experiments suggesting that Parkinson's-like degeneration of the nigrostriatal DA system can be reproduced by eliminating endogenous α-syn from DA neurons vulnerable to degeneration in PD. These studies support the tentative conclusion that α-syn elimination therapies that do not distinguish between native and abnormal forms may compromise the viability of DA neurons and should proceed with caution.