ABSTRACT
Animal models of inborn errors of metabolism are useful for investigating the pathogenesis associated with the corresponding human disease. Since the mechanisms involved in the pathophysiology of succinate semialdehyde dehydrogenase (SSADH) deficiency (Aldh5a1; OMIM 271980) are still not established, in the present study we evaluated the tissue antioxidant defences and lipid peroxidation in various cerebral structures (cortex, cerebellum, thalamus and hippocampus) and in the liver of SSADH-deficient mice. The parameters analysed were total radical-trapping antioxidant potential (TRAP) and glutathione (GSH) levels, the activities of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), as well as thiobarbituric acid-reactive substances (TBARS). We first observed that the tissue nonenzymatic antioxidant defences were significantly reduced in the SSADH-deficient animals, particularly in the liver (decreased TRAP and GSH) and in the cerebral cortex (decreased GSH), as compared to the wild-type mice. Furthermore, SOD activity was significantly increased in the liver and cerebellum, whereas the activity of CAT was significantly higher in the thalamus. In contrast, GPx activity was significantly diminished in the hippocampus. Finally, we observed that lipid peroxidation (TBARS levels) was markedly increased in the liver and cerebral cortex, reflecting a high lipid oxidative damage in these tissues. Our data showing an imbalance between tissue antioxidant defences and oxidative attack strongly indicate that oxidative stress is involved in the pathophysiology of SSADH deficiency in mice, and likely the corresponding human disorder.
Subject(s)
Antioxidants/metabolism , Brain Diseases, Metabolic, Inborn/metabolism , Brain/metabolism , Lipid Peroxidation , Liver/metabolism , Oxidative Stress , Succinate-Semialdehyde Dehydrogenase/deficiency , Animals , Brain/enzymology , Brain Diseases, Metabolic, Inborn/enzymology , Brain Diseases, Metabolic, Inborn/genetics , Catalase/metabolism , Cerebellum/enzymology , Cerebellum/metabolism , Cerebral Cortex/enzymology , Cerebral Cortex/metabolism , Disease Models, Animal , Glutathione/metabolism , Glutathione Peroxidase/metabolism , Hippocampus/enzymology , Hippocampus/metabolism , Liver/enzymology , Mice , Mice, Inbred C57BL , Mice, Knockout , Succinate-Semialdehyde Dehydrogenase/genetics , Superoxide Dismutase/metabolism , Thalamus/enzymology , Thalamus/metabolism , Thiobarbituric Acid Reactive Substances/metabolismABSTRACT
We report the clinical, biochemical and molecular findings on the first documented patient with 4-hydroxybutyric aciduria (4-HBA, McKusick 271980) from Uruguay. The patient displayed a severe picture and turned out to be homozygous for a mutation (c.1226G < A) previously shown to be associated with null enzyme activity.