Abstract
ABSTRACTMutations in the AAAS gene coding for the nuclear pore complex protein ALADIN lead to the autosomal recessive disorder triple A syndrome. Triple A patients present with a characteristic phenotype including alacrima, achalasia and adrenal insufficiency. Patient fibroblasts show increased levels of oxidative stress, and several in vitro studies have demonstrated that the nucleoporin ALADIN is involved in both the cellular oxidative stress response and adrenal steroidogenesis. It is known that ALADIN knock-out mice lack a phenotype resembling human triple A syndrome. The objective of this study was to determine whether the application of chronic oxidative stress by ingestion of paraquat would generate a triple A-like phenotype in ALADIN null mice. Adult male mice were fed either a paraquat (0.25 g/kg diet) or control diet for 11 days. After application of chronic oxidative stress, ALADIN knock-out mice presented with an unexpected compensated glutathione metabolism, but lacked a phenotype resembling human triple A syndrome. We did not observe increased levels of oxidative stress and alterations in adrenal steroidogenesis in mice depleted for ALADIN. This study stresses the species-specific role of the nucleoporin ALADIN, which in mice involves a novel compensatory mechanism for regulating the cellular glutathione redox response.
Highlights
Triple A syndrome (OMIM #231550), a rare autosomal recessive disorder, is caused by homozygous or compound heterozygous mutations in the AAAS gene encoding the nucleoporin ALADIN (Handschug et al, 2001; Tullio-Pelet et al, 2000)
Measuring the hepatic and adrenal superoxide dismutase 2 (Sod2) expression by quantitative real-time polymerase chain reaction we determined, as expected, that Sod2 expression was about twofold diminished in Aaas KO/Sod2 Het mice under a control or paraquat diet compared to wild-type (WT) and Aaas KO mice of the same diet (Fig. 1A)
In the present study we investigated the role of the nucleoporin ALADIN in chronic paraquat-induced oxidative stress in male mice
Summary
Triple A syndrome (OMIM #231550), a rare autosomal recessive disorder, is caused by homozygous or compound heterozygous mutations in the AAAS (achalasia-adrenal insufficiency-alacrima syndrome) gene encoding the nucleoporin ALADIN (alacrimaachalasia-adrenal insufficiency neurologic disorder) (Handschug et al, 2001; Tullio-Pelet et al, 2000). ALADIN is anchored within the nuclear pore complex by the transmembrane nucleoporin NDC1 [nuclear division cycle 1 homologue (Saccharomyces cerevisiae)]. Triple A patients present with the characteristic triad of adrenocorticotropic hormone-resistant adrenal insufficiency, achalasia of the stomach cardia and alacrima in combination with progressive neurological impairments (Allgrove et al, 1978). Adrenal atrophy may occur later in life and may develop gradually (Huebner et al, 2002; Milenkovic et al, 2010)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
