These facts argue against the gain-of-function synucleinopathy hypothesis, which proposes that Lewy pathology causes Parkinson's disease: (1) most brains from people without neurological symptoms have multiple pathologies; (2) neither pathology type nor distribution correlate with disease severity or progression in Parkinson's disease; (3) aggregated α-synuclein in the form of Lewy bodies is not a space-occupying lesion but the insoluble fraction of its precursor, soluble monomeric α-synuclein; (4) pathology spread is passive, occurring by irreversible nucleation, not active replication; and (5) low cerebrospinal fluid α-synuclein levels predict brain atrophy and clinical disease progression. The transformation of α-synuclein into Lewy pathology may occur as a response to biological, toxic, or infectious stressors whose persistence perpetuates the nucleation process, depleting normal α-synuclein and eventually leading to Parkinson's symptoms from neuronal death. We propose testing the loss-of-function synucleinopenia hypothesis by evaluating the clinical and neurodegenerative rescue effect of replenishing the levels of monomeric α-synuclein. •Lewy pathology is made of what once were normal α-synuclein monomers.•Once transformed into pathology, any function α-synuclein had is lost.•Pathology does not drive symptoms or cause degeneration; loss of α-synuclein does.•The synucleinopenia hypothesis is testable and falsifiable by evaluating the effect of increasing soluble α-synuclein levels.