Antibody treatment targeting nitrated alpha-synuclein counteracts protein spreading pathology

α-Synuclein nitration is a prominent post-translational modification in Parkinson’s disease, but whether nitrated α-synuclein merely reflects oxidative stress or actively contributes to pathology remains unclear. Here, we generated and characterized 6G6, an antibody selective for Tyr39-nitrated α-synuclein, and tested whether targeting this modified α-synuclein species affected pathology in different mouse models of α-synuclein aggregation and spread. In two models of α-synuclein overexpression targeting medullary vagal neurons, oxidative stress was induced by either exposure to the herbicide paraquat or transgenic heterozygous expression of the Gba1 -L444P mutation. Both conditions were characterized by robust α-synuclein spreading that was markedly counteracted by 6G6 administration. A third model consisted of an injection of α-synuclein fibrils into the striatum of α-synuclein-overexpressing mice. In this model, treatment with 6G6 protected against fibril-induced aggregate pathology and ensuing degeneration of nigral dopaminergic neurons. In a pilot human study, CSF levels of Tyr39-nitrated α-synuclein were measured and found increased in Parkinson patients as compared to controls. These findings identify Tyr39-nitrated α-synuclein as a pathogenic, therapeutically targetable α-synuclein species linking oxidative/nitrative stress to PD pathological processes.