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

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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.

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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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  1. István Sziráki

    Present address: Department of Biochemistry, IVAX Institute for Drug Research, PO Box 82, H-1325, Budapest, Hungary

Authors and Affiliations

  1. Taub Institute on Alzheimer’s Disease and Aging, Department of Pathology, Columbia University, Black Bldg 513, 650 W 168th St, New York, NY, 10032, USA

    Wai Haung Yu & Karen E. Duff

  2. Department of Neurology, Georgetown University, Building D, Room 202A, 4000 Reservoir Rd NW, Washington, DC, 20057, USA

    Yasuji Matsuoka

  3. Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd, Orangeburg, NY, 10962, USA

    Audrey Hashim, John LaFrancois & Henry Sershen

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  1. Wai Haung Yu
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Yu, W.H., Matsuoka, Y., Sziráki, I. et al. Increased Dopaminergic Neuron Sensitivity to 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) in Transgenic Mice Expressing Mutant A53T α-Synuclein. Neurochem Res 33, 902–911 (2008). https://doi.org/10.1007/s11064-007-9533-4

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