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Expression profiling reveals multiple myelin alterations in murine succinate semialdehyde dehydrogenase deficiency

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Journal of Inherited Metabolic Disease

Summary

Succinic semialdehyde dehydrogenase (SSADH) deficiency, a rare genetic defect of GABA degradation recently modelled in mice (SSADH−/− mice), manifests early absence seizures that evolve into generalized convulsive seizures and lethal status epilepticus in gene-ablated mice. Disrupted GABA homeostasis, in conjunction with the epileptic phenotype and increased gamma-hydroxybutyric acid (GHB), suggested that expression profiling with the U74Av2 Affymetrix system would reveal dysregulation of receptor genes associated with GABAergic and glutamatergic neurotransmission. Unexpectedly, we found significant downregulation for genes associated with myelin biogenesis and compaction, predominantly in hippocampus and cortex. These results were confirmed by: (1) myelin basic protein (MBP) immunohistochemistry; (2) western blotting of myelin-associated glycoprotein (MAG) and MBP; (3) qRT-PCR analyses of myelin-associated oligodendrocytic basic protein (MOBP), MAG, MBP and proteolipid protein (PLP) in hippocampus, cortex and spinal cord; (4) quantitation of ethanolamine and choline plasmalogens, all core myelin components; (5) evaluation of myelin content in brain sections employing toluidine blue staining; and (6) ultrastructural evaluation of myelin sheath thickness via electron microscopy. We speculate that increased GABA/GHB, acting through GABAergic systems, results in decreased levels of the neurosteroids progesterone and allopregnanolone [Gupta et al (2003) Ann Neurol 54(Supplement 6): S81–S90] and phosphorylation of mitogen-activated protein (MAP) kinase, with resulting myelin protein abnormalities primarily in the cortex of SSADH−/− mice.

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Authors and Affiliations

  1. Developmental Neurogenetics Research Laboratory, Barrow Neurological Institute, Phoenix, Arizona, USA

    Elizabeth A. Donarum

  2. Neurogenomics Program, Translational Genomics Research Institute, Phoenix, Arizona, USA

    Dietrich A. Stephan

  3. Departments of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon, USA

    Kay Larkin

  4. Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine, Grand Forks, North Dakota, USA

    Eric J. Murphy

  5. Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA

    Maneesh Gupta, Henry Senephansiri & K. Michael Gibson

  6. Neuroscience Associates, Knoxville, Tennessee, USA

    Robert C. Switzer

  7. Departments of Pediatrics and Neurology, Children’s National Medical Center, The George Washington University School of Medicine, Washington, D.C., USA

    Phillip L. Pearl

  8. Department of Pediatrics, Division of Neurology and The Program in Brain and Behavior, Faculty of Medicine, Hospital for Sick Children, Toronto, Ontario, Canada

    O. Carter Snead

  9. Department of Clinical Chemistry, VU Medical Center, Amsterdam, The Netherlands

    C. Jakobs

  10. Children’s Hospital of Pittsburgh, Rangos Research Center, University of Pittsburgh School of Medicine, Room 2111, 3460 Fifth Ave, Pittsburgh, PA, 15213, USA

    K. Michael Gibson

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  1. Elizabeth A. Donarum
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  2. Dietrich A. Stephan
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  8. Phillip L. Pearl
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  10. C. Jakobs
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  11. K. Michael Gibson
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Correspondence to K. Michael Gibson.

Additional information

These authors contributed equally to this study.

Communicating editor: Verena Peters

Competing interests: None declared

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Donarum, E.A., Stephan, D.A., Larkin, K. et al. Expression profiling reveals multiple myelin alterations in murine succinate semialdehyde dehydrogenase deficiency. J Inherit Metab Dis 29, 143–156 (2006). https://doi.org/10.1007/s10545-006-0247-6

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  • DOI: https://doi.org/10.1007/s10545-006-0247-6

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