Differential pathological dynamics triggered by distinct Parkinson patient-derived ?-synuclein extracts in nonhuman primates

Abstract

The presence of ?-synuclein (?-syn) aggregates, such as Lewy bodies in patients with Parkinson's disease (PD), contributes to dopaminergic cell death. Injection of PD patient-derived ?-syn in nonhuman primates has illustrated the exquisite vulnerability of primate dopaminergic neurons. Here, we aimed to elucidate the temporal and spatial pathological changes induced by two distinct ?-syn pathogenic structures, having large or small sizes. To unravel the underlying molecular pathways, we conducted a proteomic analysis of the putamen and the entorhinal cortex, two brain regions carrying notable ?-syn pathology. We demonstrate that distinct assemblies of ?-syn aggregates drive unique pathogenic changes that ultimately result in a comparable extent of nigrostriatal degeneration at the level of nigral dopaminergic neuron cell bodies and striatal dopaminergic terminals. More broadly, our findings identify pathogenic trajectories associated with large or small ?-syn aggregates, suggesting the existence of several possible concomitant pathogenic routes in PD.