International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


POSTER 143 - TOWARDS A MOUSE MODEL FOR PARKINSONíS DISEASE:† HUMANIZING THE SNCA LOCUS

D Cabin
NHGRI/NIH

2) Gispert S, 3) Murphy D, 4) Shimazu K, 4) Lu B, 1) Nussbaum R
1) NHGRI/NIH, 2) U. of Frankfurt 3) MINDS/NIH, 4) NINDS/NIH

Mutations in ?-synuclein† (SNCA) are known to cause Parkinsonís disease in a subset of familial cases.† The normal function of this protein is unknown, but it is a major component of Lewy bodies, the neuronal inclusions diagnostic for Parkinsonís disease.† We have previously shown that mice lacking Snca are depleted for a subset of synaptic vesicles in hippocampal neurons, and hippocampal slices from these animals show an attenuated response to a prolonged course of low frequency stimuli.† The mechanism by which lack of Snca causes these phenotypes is unknown.† Microarray experiments were performed to see if differences in gene expression might help in understanding Sncaís function.† No dramatic differences have been found, but there are numerous subtle changes, including a down-regulation of a subset of mitochondrial and ribosomal genes in the knockout mice.Two human SNCA transgenes were crossed onto the knockout background.†† The wild-type gene is carried on a PAC with its endogenous promoter.† A human cDNA carrying the A53T mutation is under the control of the prion promoter.† Inclusions containing SNCA were found in the brains of knockout mice carrying the human mutant cDNA transgene, but not in those carrying the wild type.† Though the expression level of the mutant transgene is low, some mice expressing only this version of the protein have developed a fast-progressing limb weakness and paralysis.†† The wild type and mutant transgenes have been homozygosed on the knockout to generate a mouse model that reflects the heterozygote status of familial Parkinsonís disease patients.


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