International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

B29. Development of Mouse Models for Parkinson's Disease

Cabin, D.E., S. Gispert, K. L. McIlwain*, R. Paylor*, B. Orrison, A. Chen, L. Garrett and R. Nussbaum
Genetic Disease Research Branch, NHGRI, NIH, Bethesda, MD.
*Baylor College of Medicine, Houston, TX.

Mutations in the alpha-synuclein gene (SNCA) are responsible for some familial forms of Parkinson's disease. The function of the SNCA protein is not known, but it is the major component of Lewy bodies, the neuronal inclusions diagnostic for Parkinson's disease. The mouse Snca gene was knocked out by replacing the second and third exons with the neomycin resistance gene. Mice homozygous for the deletion produce no alpha-syncuclein detectable on Western blots, and are viable and healthy. Thirteen littermate pairs of +/+ and -/- males were bred for behavioral testing. Statistically significant differences were seen only for two of the parameters of the open-field test. The mice were less than one year of age at the time of testing, so the pairs of animals are being aged to determine if differences in motor function will develop with time. The knockout mice have been bred to two strains of transgenic mice, one carrying the wild type human SNCA gene, the other carrying the A53T mutant version of SNCA. The wild type human transgene is carried on a PAC and is thus under the control of its endogenous promoter, while the A53T mutant transgene is a cDNA construct driven by the prion promoter. Sections of the substantia nigra from knockout animals homozygous for each transgene have been examined by immunohistochemistry. Both the wild type and the A53T transgenes are expressed in a pattern similar to that of normal mouse alpha-synuclein. Knockout animals carrying both the mutant and wild type human genes are now being bred to homozygosity for both transgenes. These animals will recapitulate the heterozygous genotype found in Parkinson's disease patients carrying the A53T mutation.

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