Oral N-Acetyl-Cysteine Attenuates Loss of Dopaminergic Terminals in α-Synuclein Overexpressing Mice

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Oral N-Acetyl-Cysteine Attenuates Loss of Dopaminergic Terminals in α-Synuclein Overexpressing Mice

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Title: Oral N-Acetyl-Cysteine Attenuates Loss of Dopaminergic Terminals in α-Synuclein Overexpressing Mice
Author: Clore, Elizabeth L.; Zheng, Kangni; Adame, Anthony; Masliah, Eliezer; Clark, Joanne; Simon, David K.

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Citation: Clark, Joanne, Elizabeth L. Clore, Kangni Zheng, Anthony Adame, Eliezer Masliah, and David K. Simon. 2010. Oral N-acetyl-cysteine attenuates loss of dopaminergic terminals in α-synuclein overexpressing mice. PLoS ONE 5(8): e12333.
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Abstract: Levels of glutathione are lower in the substantia nigra (SN) early in Parkinson's disease (PD) and this may contribute to mitochondrial dysfunction and oxidative stress. Oxidative stress may increase the accumulation of toxic forms of α-synuclein (SNCA). We hypothesized that supplementation with n-acetylcysteine (NAC), a source of cysteine – the limiting amino acid in glutathione synthesis, would protect against α-synuclein toxicity. Transgenic mice overexpressing wild-type human α-synuclein drank water supplemented with NAC or control water supplemented with alanine from ages 6 weeks to 1 year. NAC increased SN levels of glutathione within 5–7 weeks of treatment; however, this increase was not sustained at 1 year. Despite the transient nature of the impact of NAC on brain glutathione, the loss of dopaminergic terminals at 1 year associated with SNCA overexpression was significantly attenuated by NAC supplementation, as measured by immunoreactivity for tyrosine hydroxylase in the striatum (p = 0.007; unpaired, two-tailed t-test), with a similar but nonsignificant trend for dopamine transporter (DAT) immunoreactivity. NAC significantly decreased the levels of human SNCA in the brains of PDGFb-SNCA transgenic mice compared to alanine treated transgenics. This was associated with a decrease in nuclear NFκB localization and an increase in cytoplasmic localization of NFκB in the NAC-treated transgenics. Overall, these results indicate that oral NAC supplementation decreases SNCA levels in brain and partially protects against loss of dopaminergic terminals associated with overexpression of α-synuclein in this model.
Published Version: doi://10.1371/journal.pone.0012333
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2925900/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:5360628

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