Pesticide exposure exacerbates alpha-synucleinopathy in an A53T transgenic mouse model.
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 alpha-synuclein transgenic mice (M83), which develop alpha-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 alpha-synuclein pathology throughout the central nervous system including the hippocampus, cerebellum, and sensory and auditory cortices. alpha-Synuclein-associated mitochondrial degeneration was observed in M83 but not in wild-type alpha-synuclein transgenic mice. Because alpha-synuclein inclusions accumulated in pesticide-exposed M83 transgenic mice without a motor phenotype, we conclude that alpha-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 alpha-synuclein pathologies and the onset of Parkinson's-like neurodegeneration.
Norris
Erin H
EH
Center for Neurodegenerative Disease Research, Institute on Aging, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 3600 Spruce St., Maloney 3, HUP, Philadelphia, PA 19104-4283, USA.
Uryu
Kunihiro
K
Leight
Susan
S
Giasson
Benoit I
BI
Trojanowski
John Q
JQ
Lee
Virginia M-Y
VM
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000648:ultrastructure; D004357:Drug Synergism; D004781:Environmental Exposure / Q000009:adverse effects*; D005659:Fungicides, Industrial / Q000633:toxicity*; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008344:Maneb / Q000819:agonists / Q000633:toxicity*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D020125:Mutation, Missense; D010269:Paraquat / Q000819:agonists / Q000633:toxicity*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051844:alpha-Synuclein / Q000096:biosynthesis / Q000235:genetics
D005659:Fungicides, Industrial; C497604:SNCA protein, human; D051844:alpha-Synuclein; D008344:Maneb; D010269:Paraquat