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
- Kirik D, Rosenblad C, Burger C, Lundberg C, Johansen TE, Muzyczka N, Mandel RJ, Björklund A. Parkinson-like neurodegeneration induced by targeted overexpression of alpha-synuclein in the nigrostriatal system. J Neurosci. 2002 Apr 1;22(7):2780-91. PubMed.
- Lo Bianco C, Ridet JL, Schneider BL, Deglon N, Aebischer P. alpha -Synucleinopathy and selective dopaminergic neuron loss in a rat lentiviral-based model of Parkinson's disease. Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10813-8. PubMed.
- Klein RL, King MA, Hamby ME, Meyer EM. Dopaminergic cell loss induced by human A30P alpha-synuclein gene transfer to the rat substantia nigra. Hum Gene Ther. 2002 Mar 20;13(5):605-12. PubMed.
No Available Further Reading
- Kirik D, Annett LE, Burger C, Muzyczka N, Mandel RJ, Björklund A. Nigrostriatal alpha-synucleinopathy induced by viral vector-mediated overexpression of human alpha-synuclein: a new primate model of Parkinson's disease. Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2884-9. PubMed.