-Synuclein nitration is a prominent post-translational modification in Parkinson's disease, but whether nitrated -synuclein merely reflects oxidative stress or actively contributes to pathology remains unclear. Here, we generated and characterized 6G6, an antibody selective for Tyr39-nitrated -synuclein, and tested whether targeting this modified -synuclein species affected pathology in different mouse models of -synuclein aggregation and spread. In two models of -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 -synuclein spreading that was markedly counteracted by 6G6 administration. A third model consisted of an injection of -synuclein fibrils into the striatum of -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 -synuclein were measured and found increased in Parkinson patients as compared to controls. These findings identify Tyr39-nitrated -synuclein as a pathogenic, therapeutically targetable -synuclein species linking oxidative/nitrative stress to PD pathological processes.
Ulusoy, A., Wright, S., La Vitola, P., Klinger, K., Harbachova, E., Rollar, A., Xu, X., Takhi, A., Behrendt, N., Mastracci, A., Lewis, B., Chen, V., Ischiropoulos, H., Shahidi-Latham, S., Griswold-Prenner, I., Di Monte, D. A.
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