This study investigates the distinct neurotoxic effects of different α-synuclein (αSYN) strains, including oligomers, ribbons, and fibrils, after local and systemic administration in rats. The research demonstrates that αSYN strains exhibit varying capacities to seed and propagate, leading to distinct histopathological and behavioral phenotypes. Fibrils were found to be the most toxic, causing progressive motor impairment and cell death, while ribbons induced a distinct histopathological phenotype resembling Parkinson's disease (PD) and multiple system atrophy (MSA). αSYN assemblies were shown to cross the blood-brain barrier (BBB) and distribute to the central nervous system (CNS) after intravenous injection. The study also highlights that αSYN strains can amplify in vivo, with fibrils showing the highest resistance to proteinase K and the greatest capacity to propagate. The findings suggest that αSYN strains may account for the different clinical and pathological features observed in synucleinopathies. The study further indicates that the neurotoxic potential of αSYN assemblies is strain-dependent, with fibrils exhibiting the largest neurotoxic burden on the striatonigral pathway. The results emphasize the importance of targeting αSYN strains for therapeutic strategies aimed at preventing or treating synucleinopathies.This study investigates the distinct neurotoxic effects of different α-synuclein (αSYN) strains, including oligomers, ribbons, and fibrils, after local and systemic administration in rats. The research demonstrates that αSYN strains exhibit varying capacities to seed and propagate, leading to distinct histopathological and behavioral phenotypes. Fibrils were found to be the most toxic, causing progressive motor impairment and cell death, while ribbons induced a distinct histopathological phenotype resembling Parkinson's disease (PD) and multiple system atrophy (MSA). αSYN assemblies were shown to cross the blood-brain barrier (BBB) and distribute to the central nervous system (CNS) after intravenous injection. The study also highlights that αSYN strains can amplify in vivo, with fibrils showing the highest resistance to proteinase K and the greatest capacity to propagate. The findings suggest that αSYN strains may account for the different clinical and pathological features observed in synucleinopathies. The study further indicates that the neurotoxic potential of αSYN assemblies is strain-dependent, with fibrils exhibiting the largest neurotoxic burden on the striatonigral pathway. The results emphasize the importance of targeting αSYN strains for therapeutic strategies aimed at preventing or treating synucleinopathies.