Deletion of a single allele of thePex11βgene is sufficient to cause oxidative stress, delayed differentiation and neuronal death in mouse brain

Abstract

SUMMARYImpaired neuronal migration and cell death are commonly observed in patients with peroxisomal biogenesis disorders (PBDs), and in mouse models of this diseases. In Pex11β-deficient mice, we observed that the deletion of a single allele of the Pex11β gene (Pex11β+/− 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 (Pex11β−/− mice). In corresponding brain sections, cell death was rare, but differences between the genotypes were similar to those found in vitro. Because PEX11β has been implicated in peroxisomal proliferation, we searched for alterations in peroxisomal abundance in the brain of heterozygous and homozygous Pex11β-null mice compared with wild-type animals. Deletion of one allele of the Pex11β 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 Pex11β+/− mice, and to a further extent in Pex11β−/− 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 Pex11β-deficient mice. SOD2 was upregulated in neurons from Pex11β+/− mice, but not from Pex11β−/− animals, whereas the level of catalase remained unchanged in neurons from Pex11β+/− mice and was reduced in those from Pex11β−/− mice, suggesting a partial compensation of oxidative stress in the heterozygotes, but a failure thereof in the homozygous Pex11β−/− brain. In conclusion, we report the alterations in the brain caused by the deletion of a single allele of the Pex11β 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.

Compromised peroxisomes in idiopathic pulmonary fibrosis, a vicious cycle inducing a higher fibrotic response via TGF-β signaling

“…Accordingly, our findings also indicate that dysfunctional peroxisomes lead to increased cellular ROS production in IPF cells. This notion is in line with previous studies showing that the deficiency of peroxisomal proteins leads to increased ROS production and oxidative stress (10,17).…”

“…(9). Absence or dysfunction of peroxisomes results in increased cellular oxidative stress, leading to severe pathological consequences in many organ systems (10,11). Lung is one of the organs with highest exposure to various forms of reactive oxygen and nitrogen species (ROS and RNS) due to oxygen and different environmental oxidants in the inspired air, causing oxidation of cellular DNA, proteins and lipids, consequently a direct lung injury (12).…”

Coupling organelle inheritance with mitosis to balance growth and differentiation

“…Although not well studied in the epidermis, peroxisomes house the metabolic enzymes for H 2 O 2 processing, fatty acid oxidation, ether lipid synthesis, and other tissue-specific metabolic functions (26, 27). Although loss of PEX11b results in only minor changes in lipid metabolism in yeast and mammalian cells (11, 18, 20, 22, 23), mutations in PEX11b can generate a peroxisomal disease phenotype in both mice and humans (24). Thus, although required for tissue function, PEX11b’s function in peroxisome biology likely resides outside the realm of metabolism.…”

The Pex1-G844D mouse: A model for mild human Zellweger spectrum disorder

“…The first three models recapitulate multiple aspects of the most severe end of the ZSD disease spectrum, including absent peroxisome function, severe hypotonia, and neonatal lethality [24-26, 48]. Similar to humans, severe peroxisome deficiency is compatible with embryonic, but not postnatal, life in mice.…”