Pathologic Modifications of >-Synuclein in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP)Y Treated Squirrel Monkeys

>-Synuclein expression is increased in dopaminergic neurons challenged by toxic insults. Here, we assessed whether this upregulation is accompanied by pathologic accumulation of >-synuclein and protein modifications (i.e. nitration, phosphorylation, and aggregation) that are typically observed in Parkinson disease and in other synucleinopathies. A single injection of the neurotoxicant 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP) to squirrel monkeys caused a buildup of >-synuclein but not of A-synuclein or synaptophysin within nigral dopaminergic cell bodies. Immunohistochemistry and immunoelectron microscopy also revealed large numbers of dystrophic axons labeled with >-synuclein. Antibodies that recognize nitrated and phosphorylated (at serine 129) >-synuclein stained neuronal cell bodies and dystrophic axons in the midbrain of MPTPYtreated animals. After toxicant exposure, >-synuclein deposition occurred at the level of neuronal axons in which amorphous protein aggregates were observed by immunoelectron microscopy. In a subset of these axons, immunoreactivity for >-synuclein was still evident after tissue digestion with proteinase K, further indicating the accumulation of insoluble protein. These data indicate that toxic injury can induce >-synuclein modifications that have been implicated in the pathogenesis of human synucleinopathies. The findings are also consistent with a pattern of evolution of >-synuclein pathology that may begin with the accumulation and aggregation of the protein within damaged axons.