Differential pathological dynamics triggered by distinct Parkinson patient–derived α-synuclein extracts in nonhuman primates
- R. Kinet
- M. Bourdenx
- S. Dovero
- M. Darricau
- M.-L. Arotcarena
- S. Camus
- G. Porras
- M.-L. Thiolat
- I. Trigo-Damas
- S. Bohic
- M. Morari
- E. Doudnikoff
- M. Goikoetxea
- S. Claverol
- C. Tokarski
- N. Kruse
- B. Mollenhauer
- C. Estrada
- N. Garcia-Carrillo
- M. T. Herrero
- M. Vila
- J. A. Obeso
- E. Bezard
- B. Dehay
2025-06-18
The presence of α-synuclein (α-syn) aggregates, such as Lewy bodies in patients with Parkinson’s disease (PD), contributes to dopaminergic cell death. Injection of PD patient–derived α-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 α-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 α-syn pathology. We demonstrate that distinct assemblies of α-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 α-syn aggregates, suggesting the existence of several possible concomitant pathogenic routes in PD.