In this Hypothesis and Theory article we address the alpha-synuclein gain-of-function vs. loss-of-function debate as it applies to DA neuron pathology in PD. Our experimental findings in rats and non-human primates, combined with support for the concept from other reports in the literature, leads to the proposal that loss-of-function plays a significant role in this pathology. On its surface, the α-syn loss-of-function hypothesis seems counterintuitive since α-syn accumulation as aggregates, in the form of Lewy bodies, is a key neuropathologic feature of PD. However, while experimental observations largely have been interpreted as suggestive of a cytotoxic role for α-syn, it does not preclude the alternate interpretation that α-syn aggregation reflects processes that prevent α-syn from performing its normal biological functions. Our recent findings in non-human primates support the contention that α-syn loss-of-function in midbrain DA neurons accurately reproduces the pattern of nigrostriatal degeneration observed in PD, and that α-syn aggregation, acting as a “sink,” is one possible driver of this process rather than a direct toxic culprit in cell loss (Figure 2). The findings suggest reconsideration of the relationship of α-syn to PD pathogenesis and caution in the implementation of α-syn clearance therapeutic strategies that do not distinguish between natural forms and pathological forms.