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Parkinson-Like Neurodegeneration Induced by Targeted Overexpression of α-Synuclein in the Nigrostriatal System

Kirik, Deniz, Rosenblad, Carl, Burger, Corinna, Lundberg, Cecilia, Johansen, Teit E., Muzyczka, Nicholas, Mandel, Ronald J., Björklund, Anders·2002·The Journal of Neuroscience
DOI 10.1523/jneurosci.22-07-02780.2002
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Abstract

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 wild-type and A53T mutated human α-synuclein in the nigrostriatal dopamine neurons of adult rats for up to 6 months. Cellular and axonal pathology, including α-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 α-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 α-synuclein, pointing to a key role for α-synuclein in the pathogenesis of Parkinson's disease. Targeted overexpression of α-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.

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  • Viral-mediated overexpression of wild-type or mutant SNCA in nigral neurons of rodents and non-human primates produces progressive motor dysfunction resembling Parkinson's disease motor symptoms.

    “Viral-mediated overexpression of wild-type or mutant SNCA within nigral neurons of rodents and non-human primates resulted in progressive motor dysfunction resembling the motor symptoms of PD patients [4–6].”

    From RNA binding protein AUF1/HNRNPD regulates nuclear export, stability and translation of SNCA transcripts (2023) · cites this paper as [4]

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Metadata

Authors
Kirik, D., Rosenblad, C., Burger, C., Lundberg, C., Johansen, T. E., Muzyczka, N., Mandel, R. J., & Björklund, A.
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2002-04-01
Volume
22
Issue
7
Pages
2780-2791
ISSN
  • 0270-6474
  • 1529-2401
DOI
10.1523/jneurosci.22-07-02780.2002
Cited by
649
References
6
Language
en
Licence
creativecommons.org/licenses/by-nc-sa/4.0/ (vor, 183 d)

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