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

By D. Kirik, C. Rosenblad, Corinna Burger, C. Lundberg, T. Johansen, N. Muzyczka, R. Mandel, A. Björklund. Journal of Neuroscience, 2002

713 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Cognitive Neuroscience, Neurology

View Paper: https://www.semanticscholar.org/paper/4fb4ea4a33b8c68b6e371047aec8cb8d1ebb591e

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. Leonidas Stefanis
2. P. Jenner
3. S. Przedborski
4. W. Dauer
5. S. Duty
6. T. Dawson
7. Valina L. Dawson
8. H. Ko

In Cognitive Neuroscience

1. Leonidas Stefanis

In Neurology

1. Leonidas Stefanis
2. P. Jenner
3. S. Duty
4. S. Przedborski
5. W. Dauer
6. T. Dawson
7. Valina L. Dawson
8. H. Ko

Citations in the corpus

• Intravesicular Localization and Exocytosis of α-Synuclein and its Aggregates (2005, background): “Moreover, viral vectormediated expression of -syn in substantia nigra in monkeys and rats has led to nigrostriatal degeneration and LB-like inclusion bodies (Kirik et al., 2002, 2003; Lo Bianco et al., 2002).”
• Parkinson's disease: genetics and pathogenesis. (2011, background): “Additionally, numerous α-synuclein-containing aggregates in neuronal cell bodies and neurites were observed following viral-mediated expression of α-synuclein in rat (132, 134).”
• Parkinson's Disease Mechanisms and Models (2003, background): “…catalyzes the hydrolysis of C-terminal ubiquityl inclusions and other pathologic changes reminiscent ofesters and is thought to play a role in recycling ubiquitin those observed in PD (Kirik et al., 2002; Lo Bianco etligated to misfolded proteins after their degradation by al., 2002).”
• α-Synuclein in Parkinson's disease. (2012, methodology): “An alternative approach has been the viral-mediated transduction of dopaminergic neurons of the substantia nigra of rodents with a-synuclein, and this has been more successful in modeling the dopaminergic cell death aspect of the disease (Kirik et al. 2002).”
• Recombinant AAV viral vectors pseudotyped with viral capsids from serotypes 1, 2, and 5 display differential efficiency and cell tropism after delivery to different regions of the central nervous system. (2004, background): “This makes rAAV vectors valuable tools for creating animal models of diseases [22], for gene therapy applications [23–25], and for functional genomics [11,26].”
• Animal models of Parkinson's disease: a source of novel treatments and clues to the cause of the disease (2011, background): “For example, viral vector-driven over-expression of a-synuclein in both adult mice and primates has produced models that more closely reproduce the pathology of the human condition in terms of exhibiting nigro-striatal tract degeneration (Kirik et al., 2002; 2003; Lo Bianco et al., 2004).”