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Lack of Nigral Pathology in Transgenic Mice Expressing Human α-Synuclein Driven by the Tyrosine Hydroxylase Promoter

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Abstract

α-Synuclein has been identified as a major component of Lewy body inclusions, which are one of the pathologic hallmarks of idiopathic Parkinson's disease. Mutations in α-synuclein have been found to be responsible for rare familial cases of Parkinsonism. To test whether overexpression of human α-synuclein leads to inclusion formation and neuronal loss of dopaminergic cells in the substantia nigra, we made transgenic mice in which the expression of wild-type or mutant (A30P and A53T) human α-synuclein protein was driven by the promoter from the tyrosine hydroxylase gene. Even though high levels of human α-synuclein accumulated in dopaminergic cell bodies, Lewy-type-positive inclusions did not develop in the nigrostriatal system. In addition, the number of nigral neurons and the levels of striatal dopamine were unchanged relative to non-transgenic littermates, in mice up to one year of age. These findings suggest that overexpression of α-synuclein within nigrostriatal dopaminergic neurons is not in itself sufficient to cause aggregation into Lewy body-like inclusions, nor does it trigger overt neurodegenerative changes.

References (19)

  • R. Jakes et al.

    Epitope mapping of LB509, a monoclonal antibody directed against human α-synuclein

    Neurosci. Lett.

    (1999)
  • M. Sasahara et al.

    PDGF B-chain in neurons of the central nervous system, posterior pituitary, and in a transgenic model

    Cell

    (1991)
  • S.A. Banerjee et al.

    5′ flanking sequences of the rat tyrosine hydroxylase gene target accurate tissue-specific, developmental, and transsynaptic expression in transgenic mice

    J. Neurosci.

    (1992)
  • H. Braak et al.

    Pathoanatomy of Parkinson's disease

    J. Neurol.

    (2000)
  • P. Chan et al.

    (+)MK-801 does not prevent MPTP-induced loss of nigral neurons in mice

    J. Pharmacol. Exp. Ther.

    (1997)
  • M.B. Feany et al.

    A Drosophila model of Parkinson's disease

    Nature

    (2000)
  • L.S. Forno et al.

    Similarities and differences between MPTP-induced parkinsonsim and Parkinson's disease—Neuropathologic considerations

    Adv. Neurol.

    (1993)
  • M.S. Goldberg et al.

    Studies of human α-synuclein in transgenic mice

    Abstr. Soc. Neurosci.

    (2000)
  • P.J. Kahle et al.

    Subcellular localization of wild-type and Parkinson's disease-associated mutant α-synuclein in human and transgenic mouse brain

    J. Neurosci.

    (2000)
There are more references available in the full text version of this article.

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These authors contributed equally to this work.

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