Deletion of a single allele of the Pex11β gene is sufficient to cause oxidative stress, delayed differentiation and neuronal death in mouse brain

Impaired neuronal migration and cell death are commonly observed in patients with peroxisomal biogenesis disorders (PBDs), and in mouse models of this diseases. In Pex11 beta-deficient mice, we observed that the deletion of a single allele of the Pex11 beta gene (Pex11 beta(+/-) heterozygous mice) caused cell death in primary neuronal cultures prepared from the neocortex and cerebellum, although to a lesser extent as compared with the homozygous-null animals (Pex11 beta(-/-) mice). In corresponding brain sections, cell death was rare, but differences between the genotypes were similar to those found in vitro. Because Pex11 beta has been implicated in peroxisomal proliferation, we searched for alterations in peroxisomal abundance in the brain of heterozygous and homozygous Pex11 beta-null mice compared with wild-type animals. Deletion of one allele of the Pex11 beta gene slightly increased the abundance of peroxisomes, whereas the deletion of both alleles caused a 30% reduction in peroxisome number. The size of the peroxisomal compartment did not correlate with neuronal death. Similar to cell death, neuronal development was delayed in Pex11 beta(+/-) mice, and to a further extent in Pex11 beta(-/-) mice, as measured by a reduced mRNA and protein level of synaptophysin and a reduced protein level of the mature isoform of MAP2. Moreover, a gradual increase in oxidative stress was found in brain sections and primary neuronal cultures from wild-type to heterozygous to homozygous Pex11 beta-deficient mice. SOD2 was upregulated in neurons from Pex11 beta(+/-) mice, but not from Pex11 beta(-/-) animals, whereas the level of catalase remained unchanged in neurons from Pex11 beta(+/-) mice and was reduced in those from Pex11 beta(-/-) mice, suggesting a partial compensation of oxidative stress in the heterozygotes, but a failure thereof in the homozygous Pex11 beta(-/-) brain. In conclusion, we report the alterations in the brain caused by the deletion of a single allele of the Pex11 beta gene. Our data might lead to the reconsideration of the clinical treatment of PBDs and the common way of using knockout mouse models for studying autosomal recessive diseases.