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Viral Transgene Models Parkinson's in Primate
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28 February 2003. Last year, three separate laboratories managed to create impressive Parkinson's disease models by transferring human α-synuclein via viral vectors to mice (Kirik et al., 2002; Lo Bianco et al., 2002; Klein et al., 2002). This approach has now panned out in a primate model, as well, report Deniz Kirik and Anders Bjorklund of Lund University in Sweden, and their collaborators at the University of Hertfordshire in Hatfield, the United Kingdom, and at the University of Florida in Gainesville.
In the February 24 online Proceeding of the National Academy of Sciences, Kirik and colleagues describe an experiment similar to their rat model (see ARF related news story). They introduced genes for either wild-type or mutant (A53T) human α-synuclein into adult marmoset monkeys via a recombinant adeno-associated (rAAV) vector.
As with the mice, either wild-type or mutant human α-synuclein caused the monkeys to develop severe neuronal pathology in the substantia nigra, including α-synuclein-positive cytoplasmic inclusions and granular deposits; swollen, dystrophic, and fragmented neurites; and shrunken and pyknotic, densely α-synuclein-positive perikarya. Sixteen weeks after transduction of the genes, the monkeys had lost 30 to 60 percent of dopaminergic neurons in the substantia nigra, as well as 40 to 50 percent of the dopaminergic innervation of the striatum. The histologic data were accompanied by behavioral impairment in the form a head position bias compatible with this level of nigrostriatal dopamine deficit.
"Viral vectors, and the new-generation high-titer rAAV vectors in particular, provide new, efficient tools for cell-specific, targeted transgenesis in the brain.... Because rAAV vectors can be administered repeatedly to the same cells, they will be interesting also as tools for the expression of genes and intracellular factors that may block or interfere with critical pathogenetic processes (such as formation of toxic fibrils or protein aggregates in rAAV-α-syn-treated animals) and for the exploration of new molecular targets for therapeutic purposes," conclude the authors.-Hakon Heimer.
Reference:
Kirik D, Annett LE, Burger C, Muzyczka N, Mandel RJ, Bjorklund A. Nigrostriatal α-synucleinopathy induced by edcombinant adeno-associated virus vector-mediated overexpression of human α-synuclein: A new primate model of Parkinson's disease. Proc Nat Acad Sci U S A. 2003. Abstract
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Comments on News and Primary Papers |
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Comment by: Ronald Klein
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Submitted 28 February 2003
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Posted 28 February 2003
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The findings by Kirik et al. are a breakthrough because they provide a human-like model of Parkinson's disease and make the earlier findings in rats ( Kirik et al., 2002; Lo Bianco et al., 2002; Klein et al., 2002) even more relevant for Parkinson's disease. The authors note the involvement of α-synuclein and oxidative stress. To pursue this, and probably in rats for feasibility, subjects will be monitored for markers of oxidative stress and mitochondrial function after α-synuclein gene transfer. Alternatively, diets either rich or deficient in antioxidants can be tested for their effects on the α-synuclein vector-induced disease.
 View all comments by Ronald Klein |
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Comment by: James Galvin, ARF Advisor
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Submitted 3 March 2003
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Posted 3 March 2003
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"A model, a model...my kingdom for a model!"
At last, a model that appears to recapitulate not only some of the motor features of Parkinson's disease, but also the pathology. Even as we have come to understand the importance of α-synuclein in the pathophysiology of PD and other Lewy body disorders, the field has been hampered by the paucity of animal models that recapitulate the major pathology, particularly in regard to the substantia nigra. Kirik and colleagues should be applauded for at last contributing a primate model that is likely to advance the field. In addition, this technology can potentially be applied to rodent models that will substantially shorten the study time to test hypotheses regarding oxidative stress, free radicals, and mitochondrial function and the development of Parkinson's disease.—James Galvin, Washington University School of Medicine, St. Louis, Missouri.
View all comments by James Galvin |
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Comment by: Curt Freed
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Submitted 3 March 2003
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Posted 3 March 2003
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I liked the article on unilateral α-synuclein expression in the marmoset monkey as a model of Parkinson’s. The biggest problem with the model is that it has minimal behavioral effects compared to the MPTP model. With MPTP injected unilaterally in the internal carotid artery, the opposite side of the body becomes strongly Parkinsonian with slow movements of the arm and leg on that side. When animals are given apomorphine or amphetamine, they circle intensely—after amphetamine, in a direction towards the side of the lesion, and with apomorphine, in a direction opposite to the side of the lesion. For therapeutic interventions such as neurotransplantation, a robust behavioral component is essential. It is likely that dopamine depletion on the lesioned side was not severe enough to see strongly lateralized behavioral effects. Dopamine concentrations in the striatum and substantia nigra are not reported, but cell loss was 30 to 60 percent. In rats, dopamine concentrations in striatum have to be reduced by 95 percent to see drug-induced circling.
The primary value of the marmoset...
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I liked the article on unilateral α-synuclein expression in the marmoset monkey as a model of Parkinson’s. The biggest problem with the model is that it has minimal behavioral effects compared to the MPTP model. With MPTP injected unilaterally in the internal carotid artery, the opposite side of the body becomes strongly Parkinsonian with slow movements of the arm and leg on that side. When animals are given apomorphine or amphetamine, they circle intensely—after amphetamine, in a direction towards the side of the lesion, and with apomorphine, in a direction opposite to the side of the lesion. For therapeutic interventions such as neurotransplantation, a robust behavioral component is essential. It is likely that dopamine depletion on the lesioned side was not severe enough to see strongly lateralized behavioral effects. Dopamine concentrations in the striatum and substantia nigra are not reported, but cell loss was 30 to 60 percent. In rats, dopamine concentrations in striatum have to be reduced by 95 percent to see drug-induced circling.
The primary value of the marmoset model is histologic. It shows that overexpression of α-synuclein can cause protein deposits in primate dopamine neurons and subsequent death of cells. We have shown this result in tissue culture experiments with rat and human embryonic dopamine neurons (Zhou et al., 2000 and Zhou et al., 2002), and a similar result was published in rats in 2002. The monkey outcome published by Kirik, et al. is important because it shows that adult primate dopamine neurons can suffer the same fate in the intact animal.
View all comments by Curt Freed |
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