Rollar, A. | Search bioRxiv

bioRxiv2026

Antibody treatment targeting nitrated alpha-synuclein counteracts protein spreading pathology

-Synuclein nitration is a prominent post-translational modification in Parkinsons 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.

neuroscience↗

bioRxiv2024

Mitochondrial oxidant stress promotes alpha-synuclein aggregation and spreading in mice with mutated glucocerebrosidase

Mutations of the glucocerebrosidase-encoding gene, GBA1, are common risk factors for Parkinsons disease. Although only a minority of mutation-carrying individuals develops the disease, the mechanisms of neuronal vulnerability predisposing to pathology conversion remain largely unclear. In this study, heterozygous expression of a common glucocerebrosidase variant, namely the L444P mutation, was found to exacerbate -synuclein aggregation and spreading in a mouse model of Parkinson-like pathology targeting neurons of the medullary vagal system. These neurons are primary sites of -synuclein lesions in Parkinsons disease and were shown here to become more vulnerable to oxidative stress after L444P expression. Nitrative burden paralleled the enhanced formation of reactive oxygen species within vagal neurons expressing mutated glucocerebrosidase, as indicated by pronounced accumulation of nitrated -synuclein. A causal relationship linked mutation-induced oxidative stress to enhanced -synuclein pathology that could indeed be rescued by neuronal overexpression of the mitochondrial antioxidant enzyme superoxide dismutase 2. Further evidence supported a key involvement of mitochondria as sources of reactive oxygen species as well as targets of oxidative and nitrative damage within L444P-expressing neurons. Scavenging of oxygen species by superoxide dismutase 2 effectively counteracted deleterious nitrative reactions and prevented nitrated -synuclein burden. Taken together, these findings support the conclusion that enhanced vulnerability to mitochondrial oxidative stress conferred by glucocerebrosidase mutations should be considered an important mechanism predisposing to Parkinsons disease pathology, particularly in brain regions targeted by -synuclein aggregation and involved in -synuclein spreading.

neuroscience↗