Regular Articles
Pesticide Exposure Exacerbates α-Synucleinopathy in an A53T Transgenic Mouse Model

https://doi.org/10.2353/ajpath.2007.060359Get rights and content

The factors initiating or contributing to the pathogenesis of Parkinson's disease and related neurodegenerative synucleinopathies are still largely unclear, but environmental factors such as pesticides have been implicated. In this study, A53T mutant human α-synuclein transgenic mice (M83), which develop α-synuclein neuropathology, were treated with the pesticides paraquat and maneb (either singly or together), and their effects were analyzed. Immunohistochemical and biochemical analyses showed that chronic treatment of M83 transgenic mice with both pesticides (but not with either pesticide alone) drastically increased neuronal α-synuclein pathology throughout the central nervous system including the hippocampus, cerebellum, and sensory and auditory cortices. α-Synuclein-associated mitochondrial degeneration was observed in M83 but not in wild-type α-synuclein transgenic mice. Because α-synuclein inclusions accumulated in pesticide-exposed M83 transgenic mice without a motor phenotype, we conclude that α-synuclein aggregate formation precedes disease onset. These studies support the notion that environmental factors causing nitrative damage are closely linked to mechanisms underlying the formation of α-synuclein pathologies and the onset of Parkinson's-like neurodegeneration.

Cited by (0)

Supported by National Institutes of Health grants AG09215, AG10124, and NS044233. J.Q.T. is the William Maul Measey-Truman G. Schnabel, Jr., Professor of Geriatric Medicine and Gerontology. V.M.-Y.L. is the John H. Ware Third Chair of Alzheimer's disease research.

E.H.N. and K.U. contributed equally to the manuscript.

Supplemental material for this article can be found on http://ajp.amjpathol.org.

View Abstract