Mutation frequency is reduced in the cerebellum of Big Blue (R) mice overexpressing a human wild type SOD1 gene

Amyotrophic lateral sclerosis (ALS) is a progressive paralytic disorder cau sed by motor neuron degeneration. A similar disease phenotype is observed i n mice overexpressing a mutant human hSOD1 gene(G93A, 1Gurd(1)). Mice trans genic for lad (Big Blue(R)) and human mutant (1Gurd(1), Mut hSOD1) or wild type (2Gur, Wt hSOD1) SOD1 genes were used to examine spontaneous mutation, oxidative DNA damage. and neurodegeneration in vivo. The frequency and pat tern of spontaneous mutation were determined for forebrain (90% glia), cere bellum (90% neurons) and thymus from 5-month-old male mice. Mutation freque ncy is not elevated significantly and mutation pattern is unaltered in Mut hSOD1 mice compared to control mice. Mutation frequency is reduced signific antly in the cerebellum of Wt hSOD1 mice (1.6 x 10(-5). P = 0.0093; Fisher' s Exact Test) compared to mice without a human transgene (2.7 x 10(-5)). Mu tation pattern is unaltered. This first report of an endogenous factor that can reduce in vivo, the frequency of spontaneous mutation suggests potenti al strategies for lowering mutagenesis related to aging, neurodegeneration, and carcinogenesis. (C) 2001 Elsevier Science B.V. All rights reserved.