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The Journal of Neuroscience, April 1, 2002, 22(7):2780-2791

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

Deniz Kirik¹, Carl Rosenblad², Corinna Burger³, Cecilia Lundberg¹, Teit E. Johansen², Nicholas Muzyczka³, Ronald J. Mandel⁴, and Anders Björklund¹

¹ Wallenberg Neuroscience Center, Department of Physiological Sciences, Division of Neurobiology, Lund University, 221 84, Lund, Sweden, ² NsGene A/S, 2750, Ballerup, Denmark, and Departments of ³ Molecular Genetics and Microbiology and ⁴ Neuroscience, McKnight Brain Institute and Powell Gene Therapy Center, University of Florida, Gainesville, Florida 32610

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

Key words: Parkinson's disease; adeno-associated virus vector; neurodegeneration; dopamine; tyrosine hydroxylase; nigral inclusion

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Copyright © 2002 Society for Neuroscience  0270-6474/02/2272780-12$05.00/0

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