International Mammalian Genome Society


The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

F17 Humanizing the Mouse a-synuclein Locus - Development of Mouse Models for Parkinson's Disease

Cabin, D., S. Gispert, B. Orrison, A. Chen, L. Garrett and R. Nussbaum. Laboratory for Genetic Disease Research, NHGRI, NIH, Bethesda, MD

Mutations in the a-synuclein gene (SNCA) were the first to be associated with familial forms of Parkinson's disease. The gene encodes a major component of Lewy bodies, the neuronal inclusions diagnostic for Parkinson's disease. The mouse homolog was mapped to mouse chromosome 6 (MMU6) at 26.9 cM on the Jackson Laboratory BSS backcross mapping panel. This extends a small region of shared synteny between MMU6 and human chromosome 4, to which SNCA was previously mapped. The only phenotype mapped to this region of MMU6 is lc, due to mutations in Grid2. As the first step in developing animal models for the disease, the a-synuclein locus has been knocked out in the mouse by replacing the second and third coding exons with the neomycin resistance gene. Mice homozygous for the deletion produce no a-synuclein detectable by protein blotting, are viable, and have no obvious phenotypes. Matched pairs of +/+ and -/- males are being bred for behavioral testing, and mutant animals are being aged to determine if any phenotypes develop late in life. The -/- animals are also being bred to mice transgenic for both the human wild type and the A53T mutant versions of SNCA. The wild type human gene is carried on a PAC and is under the control of its endogenous promoter; the A53T mutant transgenic animals carry a cDNA construct driven by the prion promoter. The wild type transgenic animals carry about 25 copies of the PAC, and the A53T mutant transgene is present at more than 10 copies. Intercrosses of animals carrying both transgenes on a +/- a-synuclein background are in progress. Animals that carry both these transgenes on the mouse null background will mimic the situation seen in a familial form of Parkinson's disease.

 


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