This study investigates the distinct pathological effects of different strains of α-synuclein (αSYN) after local and systemic administration. αSYN is a protein implicated in neurodegenerative diseases such as Parkinson's Disease (PD), Dementia with Lewy Bodies (DLB), and Multiple System Atrophy (MSA). The authors found that αSYN strains, characterized by their conformation and seeding propensity, lead to distinct histopathological and behavioral phenotypes. αSYN oligomers, ribbons, and fibrils were injected into the rat brain, and their properties were assessed. Fibrils were found to be the major toxic species, causing progressive motor impairment and cell death. Ribbons, on the other hand, induced a distinct histopathological phenotype with features of both PD and MSA. Additionally, αSYN assemblies crossed the blood-brain barrier and distributed to the central nervous system after intravenous injection. The study demonstrates that different αSYN strains have differential seeding capacities, leading to strain-specific pathology and neurotoxic phenotypes. These findings highlight the importance of understanding the structural characteristics of αSYN strains in the development of therapeutic strategies aimed at preventing or mitigating synucleinopathies.This study investigates the distinct pathological effects of different strains of α-synuclein (αSYN) after local and systemic administration. αSYN is a protein implicated in neurodegenerative diseases such as Parkinson's Disease (PD), Dementia with Lewy Bodies (DLB), and Multiple System Atrophy (MSA). The authors found that αSYN strains, characterized by their conformation and seeding propensity, lead to distinct histopathological and behavioral phenotypes. αSYN oligomers, ribbons, and fibrils were injected into the rat brain, and their properties were assessed. Fibrils were found to be the major toxic species, causing progressive motor impairment and cell death. Ribbons, on the other hand, induced a distinct histopathological phenotype with features of both PD and MSA. Additionally, αSYN assemblies crossed the blood-brain barrier and distributed to the central nervous system after intravenous injection. The study demonstrates that different αSYN strains have differential seeding capacities, leading to strain-specific pathology and neurotoxic phenotypes. These findings highlight the importance of understanding the structural characteristics of αSYN strains in the development of therapeutic strategies aimed at preventing or mitigating synucleinopathies.