Cerebellar purkinje cell loss in heterozygous Rora+/- mice:: A longitudinal study

The staggerer (sg) mutation is a spontaneous deletion in the Rora gene that prevents the translation of the ligand-binding domain (LBD), leading to the loss of ROR alpha activity. The homozygous Rora(sg/sg) mutant mouse, whose most obvious phenotype is ataxia associated with cerebellar degeneration, also displays a variety of other phenotypes. The heterozygous Rora(+/sg) is able to develop a cerebellum that is qualitatively normal but which suffers a significant loss of cerebellar neuronal cells with advancing age. A truncated protein synthesized by the mutated allele may play a role both in Rora(sg/sg) and Rora(+/sg). To determine the effects during life span of true haplo-insufficiency of the ROR alpha protein, derived from the invalidation of the gene, we compared the evolution of Purkinje cell numbers in heterozygous Rora knock-out males (Rora(+/-)) and in their wild-type counterparts from 1 to 24 months of age. We also compared the evolution of Purkinje cell (PC) numbers in Rora(+/-) land Rora(+/sg) males from 1 to 9 months. The main finding is that in Rora(+/-) mice, for which only one-half the normal amount of protein is produced, the deficit was established as early as 1 month and did not change during the animals' adult lifespans. Thus, the effects of aging on PC number were apparent much earlier in Rora(+/-) than in Rora(+/sg) , although at 24 months of age the degrees of deficit were similar.