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Oral N-acetyl-cysteine attenuates loss of dopaminergic terminals in alpha-synuclein overexpressing mice.

Clark J, Clore EL, Zheng K, Adame A, Masliah E, Simon DK - PLoS ONE (2010)

Bottom Line: 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.This was associated with a decrease in nuclear NFkappaB localization and an increase in cytoplasmic localization of NFkappaB 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 alpha-synuclein in this model.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.

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 alpha-synuclein (SNCA). We hypothesized that supplementation with n-acetylcysteine (NAC), a source of cysteine--the limiting amino acid in glutathione synthesis, would protect against alpha-synuclein toxicity. Transgenic mice overexpressing wild-type human alpha-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 NFkappaB localization and an increase in cytoplasmic localization of NFkappaB 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 alpha-synuclein in this model.

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Performance on the Pole Test was unaffected by SNCA-overexpression or NAC treatment.A. Time for the mouse to turn on the pole and face downwards (Tturn). B. Time for the mouse to reach the bottom of the pole (TLA). There were no significant differences between the groups tested. WT ALA N = 12, WT NAC N-12, TG ALA N = 13, TG NAC N = 16.
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pone-0012333-g007: Performance on the Pole Test was unaffected by SNCA-overexpression or NAC treatment.A. Time for the mouse to turn on the pole and face downwards (Tturn). B. Time for the mouse to reach the bottom of the pole (TLA). There were no significant differences between the groups tested. WT ALA N = 12, WT NAC N-12, TG ALA N = 13, TG NAC N = 16.

Mentions: Each cohort of mice was tested on a battery of motor coordination tests at 3, 6 and 12 months of age, including rotarod testing, the pole test, and nest construction. We detected no impairments of motor coordination in any of the groups tested at any of the time points tested. Only data from the rotarod (and pole test) at 12 months of age is shown (Fig. 6 & 7) and is presented in a style to allow for comparison with previously published work [20].


Oral N-acetyl-cysteine attenuates loss of dopaminergic terminals in alpha-synuclein overexpressing mice.

Clark J, Clore EL, Zheng K, Adame A, Masliah E, Simon DK - PLoS ONE (2010)

Performance on the Pole Test was unaffected by SNCA-overexpression or NAC treatment.A. Time for the mouse to turn on the pole and face downwards (Tturn). B. Time for the mouse to reach the bottom of the pole (TLA). There were no significant differences between the groups tested. WT ALA N = 12, WT NAC N-12, TG ALA N = 13, TG NAC N = 16.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2925900&req=5

pone-0012333-g007: Performance on the Pole Test was unaffected by SNCA-overexpression or NAC treatment.A. Time for the mouse to turn on the pole and face downwards (Tturn). B. Time for the mouse to reach the bottom of the pole (TLA). There were no significant differences between the groups tested. WT ALA N = 12, WT NAC N-12, TG ALA N = 13, TG NAC N = 16.
Mentions: Each cohort of mice was tested on a battery of motor coordination tests at 3, 6 and 12 months of age, including rotarod testing, the pole test, and nest construction. We detected no impairments of motor coordination in any of the groups tested at any of the time points tested. Only data from the rotarod (and pole test) at 12 months of age is shown (Fig. 6 & 7) and is presented in a style to allow for comparison with previously published work [20].

Bottom Line: 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.This was associated with a decrease in nuclear NFkappaB localization and an increase in cytoplasmic localization of NFkappaB 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 alpha-synuclein in this model.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.

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 alpha-synuclein (SNCA). We hypothesized that supplementation with n-acetylcysteine (NAC), a source of cysteine--the limiting amino acid in glutathione synthesis, would protect against alpha-synuclein toxicity. Transgenic mice overexpressing wild-type human alpha-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 NFkappaB localization and an increase in cytoplasmic localization of NFkappaB 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 alpha-synuclein in this model.

Show MeSH
Related in: MedlinePlus