Parkinson's disease and multiple system atrophy have distinct α-synuclein seed characteristics

Parkinson's disease (PD) and multiple system atrophy (MSA) are distinct clinical syndromes characterized by the pathological accumulation of alpha-synuclein (alpha-syn) protein fibrils in neurons and glial cells. These disorders and other neurodegenerative diseases may progress via prion-like mechanisms. The prion model of propagation predicts the existence of "strains" that link pathological aggregate structure and neuropathology. Prion strains are aggregated conformers that stably propagate in vivo and cause disease with defined incubation times and patterns of neuropathology. Indeed, tau prions have been well defined, and research suggests that both alpha-syn and beta-amyloid may also form strains. However, there is a lack of studies characterizing PD- versus MSA-derived alpha-syn strains or demonstrating stable propagation of these unique conformers between cells or animals. To fill this gap, we used an assay based on FRET that exploits a HEK293T "biosensor" cell line stably expressing alpha-syn (A53T)-CFP/YFP fusion proteins to detect alpha-syn seeds in brain extracts from PD and MSA patients. Both soluble and insoluble fractions of MSA extracts had robust seeding activity, whereas only the insoluble fractions of PD extracts displayed seeding activity. The morphology of MSA-seeded inclusions differed from PD-seeded inclusions. These differences persisted upon propagation of aggregation to second-generation biosensor cells. We conclude that PD and MSA feature alpha-syn conformers with very distinct biochemical properties that can be transmitted to alpha-syn monomers in a cell system. These findings are consistent with the idea that distinct alpha-syn strains underlie PD and MSA and offer possible directions for synucleinopathy diagnosis.