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

α-Synuclein expression is increased in dopaminergic neurons challenged by toxic insults. Here, we assessed whether this upregulation is accompanied by pathological accumulation of α-synuclein and protein modifications (i.e. nitration, phosphorylation and aggregation) that are typically observed in P...

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Published in:Journal of neuropathology and experimental neurology 2008-08, Vol.67 (8), p.793-802
Main Authors: McCormack, Alison L., Mak, Sally K., Shenasa, Maryam, Langston, William J., Forno, Lysia S., Di Monte, Donato A.
Format: Article
Language:English
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Summary:α-Synuclein expression is increased in dopaminergic neurons challenged by toxic insults. Here, we assessed whether this upregulation is accompanied by pathological accumulation of α-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-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to squirrel monkeys caused a buildup of α-synuclein but not of β-synuclein or synaptophysin within nigral dopaminergic cell bodies. Immunohistochemistry and immunoelectron microscopy (IEM) also revealed large numbers of dystrophic axons labeled with α-synuclein. Antibodies that recognize nitrated and phosphorylated (at serine 129) α-synuclein stained neuronal cell bodies and dystrophic axons in the midbrain of MPTP-treated animals. Following toxicant exposure, α-synuclein deposition occurred at the level of neuronal axons in which amorphous protein aggregates were demonstrated by IEM. In a subset of these axons, immunoreactivity for α-synuclein was evident after tissue digestion with proteinase K, further indicating the accumulation of insoluble protein. These data indicate that toxic injury can induce the α-synuclein modifications that have been implicated in the pathogenesis of human synucleinopathies. The findings are also consistent with a pattern of evolution of α-synuclein pathology that may begin with the accumulation and aggregation of the protein within damaged axons.
ISSN:0022-3069
DOI:10.1097/NEN.0b013e318180f0bd