Journal
JOURNAL OF NEUROCHEMISTRY
Volume 115, Issue 6, Pages 1363-1373Publisher
WILEY
DOI: 10.1111/j.1471-4159.2010.07036.x
Keywords
alpha-synuclein; dopaminergic neurons; iron; oxidative; paraquat; parkinsonism
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Funding
- National Institutes of Health [U54 ES12077]
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As Parkinson's disease appears to be a multifactoral disorder, the use of animal models to investigate combined effects of genetic and environmental risk factors are of great importance especially in the context of aging which is the single major risk factor for the disorder. Here, we assessed the combined effects of neonatal iron feeding and environmental paraquat exposure on age-related nigrostriatal degeneration in transgenic mice expressing the A53T familial mutant form of human alpha-synuclein within these neurons. We report here that A53T alpha-synuclein mice exhibit greater susceptibility to paraquat. Increased oral intake of iron in the neonatal period leads to a progressive age-related enhancement of dopaminergic neurodegeneration associated with paraquat neurotoxicity. Furthermore, neurodegeneration associated with these combined genetic and environmental risk factors could be attenuated by systemic treatment with the bioavailable antioxidant compound EUK-189. These data suggest that environmental factors previously identified as contributors to neurodegeneration associated with sporadic Parkinson's disease may also be candidates for observed variations in symptoms and disease progression in monogenic forms and that this may mechanistically involve increased levels of oxidatively-induced post-translational nitration of alpha-synuclein.
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