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Parkinson-like neurodegeneration induced by targeted overexpression of alpha-synuclein in the nigrostriatal system

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Author

Summary, in English

Recombinant adeno-associated viral vectors display efficient tropism for transduction of the dopamine neurons of the substantia nigra. Taking advantage of this unique property of recombinant adeno-associated viral vectors, we expressed wildtype and A53T mutated human alpha-synuclein in the nigrostriatal dopamine neurons of adult rats for up to 6 months. Cellular and axonal pathology, including alpha-synuclein-positive cytoplasmic inclusions and swollen, dystrophic neurites similar to those seen in brains from patients with Parkinson's disease, developed progressively over time. These pathological alterations occurred preferentially in the nigral dopamine neurons and were not observed in other nondopaminergic neurons transduced by the same vectors. The degenerative changes were accompanied by a loss of 30-80% of the nigral dopamine neurons, a 40-50% reduction of striatal dopamine, and tyrosine hydroxylase levels that was fully developed by 8 weeks. Significant motor impairment developed in those animals in which dopamine neuron cell loss exceeded a critical threshold of 50-60%. At 6 months, signs of cell body and axonal pathology had subsided, suggesting that the surviving neurons had recovered from the initial insult, despite the fact that alpha-synuclein expression was maintained at a high level. These results show that nigral dopamine neurons are selectively vulnerable to high levels of either wild-type or mutant alpha-synuclein, pointing to a key role for alpha-synuclein in the pathogenesis of Parkinson's disease. Targeted overexpression of alpha-synuclein in the nigrostriatal system may provide a new animal model of Parkinson's disease that reproduces some of the cardinal pathological, neurochemical, and behavioral features of the human disease.

Department/s

Publishing year

2002

Language

English

Pages

2780-2791

Publication/Series

Journal of Neuroscience

Volume

22

Issue

7

Document type

Journal article

Publisher

Society for Neuroscience

Topic

  • Neurosciences

Keywords

  • tyrosine hydroxylase
  • nigral inclusion
  • dopamine
  • neurodegeneration
  • Parkinson's disease
  • adeno-associated virus vector

Status

Published

Research group

  • Neurobiology

ISBN/ISSN/Other

  • ISSN: 1529-2401