Deletion of a single allele of the Pex11ß gene is sufficient to cause oxidative stress, delayed differentiation and neuronal death in mouse brain.
Dis Model Mech
; 5(1): 125-40, 2012 Jan.
Article
en En
| MEDLINE
| ID: mdl-21954064
ABSTRACT
Impaired neuronal migration and cell death are commonly observed in patients with peroxisomal biogenesis disorders (PBDs), and in mouse models of this diseases. In Pex11ß-deficient mice, we observed that the deletion of a single allele of the Pex11ß gene (Pex11ß(+/-) 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 (Pex11ß(-/-) mice). In corresponding brain sections, cell death was rare, but differences between the genotypes were similar to those found in vitro. Because PEX11ß has been implicated in peroxisomal proliferation, we searched for alterations in peroxisomal abundance in the brain of heterozygous and homozygous Pex11ß-null mice compared with wild-type animals. Deletion of one allele of the Pex11ß 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 Pex11ß(+/-) mice, and to a further extent in Pex11ß(-/-) 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 Pex11ß-deficient mice. SOD2 was upregulated in neurons from Pex11ß(+/-) mice, but not from Pex11ß(-/-) animals, whereas the level of catalase remained unchanged in neurons from Pex11ß(+/-) mice and was reduced in those from Pex11ß(-/-) mice, suggesting a partial compensation of oxidative stress in the heterozygotes, but a failure thereof in the homozygous Pex11ß(-/-) brain. In conclusion, we report the alterations in the brain caused by the deletion of a single allele of the Pex11ß 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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Encéfalo
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Diferenciación Celular
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Eliminación de Gen
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Estrés Oxidativo
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Alelos
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Proteínas de la Membrana
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Neuronas
Límite:
Animals
Idioma:
En
Revista:
Dis Model Mech
Asunto de la revista:
MEDICINA
Año:
2012
Tipo del documento:
Article
País de afiliación:
Alemania