Neurochemical Research

, Volume 33, Issue 5, pp 902–911 | Cite as

Increased Dopaminergic Neuron Sensitivity to 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) in Transgenic Mice Expressing Mutant A53T α-Synuclein

  • Wai Haung Yu
  • Yasuji Matsuoka
  • István Sziráki
  • Audrey Hashim
  • John LaFrancois
  • Henry Sershen
  • Karen E. Duff
Original Paper

Abstract

Familial Parkinson’s disease (PD) has been linked to point mutations and duplication of the α-synuclein gene and mutant α-synuclein expression increases the vulnerability of neurons to exogenous insults. In this study, we analyzed the levels of dopamine and its metabolites in the olfactory bulb (OB), and nigrostriatal regions of transgenic mice expressing human, mutant A53T α-synuclein (α-syn tg) and their non-transgenic (ntg) littermates using a sub-toxic, moderate dose of MPTP to determine if mutant human α-synuclein sensitizes the central dopaminergic systems to oxidative stress. We observed that after a single, sub-lethal MPTP injection, dopamine levels were reduced in striatum and SN in both the α-syn tg and ntg mice. In the olfactory bulb, a region usually resistant to MPTP toxicity, levels were reduced only in the α-syn tg mice. In addition, we identified a significant increase in dopamine metabolism in the α-syn transgenic, but not ntg mice. Finally, MPTP treatment of α-syn tg mice was associated with a marked elevation in the oxidative product, 3-nitrotyrosine that co-migrated with α-synuclein. Cumulatively, the data support the hypothesis that mutant α-synuclein sensitizes dopaminergic neurons to neurotoxic insults and is associated with greater oxidative stress. The α-syn tg line is therefore useful to study the genetic and environmental inter-relationship in PD.

Keywords

Mutant α-synuclein Transgenic mice MPTP Dopamine Tyrosine hydroxylase Oxidative stress Parkinson’s disease 

Abbreviations

DA

Dopamine

DOPAC

Homovanillic acid

HVA

Dihydroxyphenyl-acetic acid

ip

Intraperitoneal

LB

Lewy body

MANOVA

Multivariant analysis of variance

MPP+

1-Methyl-4-phenylpyridinium

MPTP

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

ntg

Non-transgenic

3-NT

3-Nitrotyrosine

PD

Parkinson’s disease

TH

Tyrosine hydroxylase

α-syn tg

Human mutant α-synuclein (A53T) transgenic mouse

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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Wai Haung Yu
    • 1
  • Yasuji Matsuoka
    • 2
  • István Sziráki
    • 3
  • Audrey Hashim
    • 4
  • John LaFrancois
    • 4
  • Henry Sershen
    • 4
  • Karen E. Duff
    • 1
  1. 1.Taub Institute on Alzheimer’s Disease and Aging, Department of PathologyColumbia UniversityNew YorkUSA
  2. 2.Department of NeurologyGeorgetown UniversityWashingtonUSA
  3. 3.Department of BiochemistryIVAX Institute for Drug ResearchBudapestHungary
  4. 4.Nathan S. Kline Institute for Psychiatric ResearchOrangeburgUSA

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