Comparative genomics of aldehyde dehydrogenase 5a1 (succinate semialdehyde dehydrogenase) and accumulation of gamma-hydroxybutyrate associated with its deficiency
<p>Abstract</p> <p>Succinic semialdehyde dehydrogenase (SSADH; aldehyde dehydrogenase 5A1 [ALDH5A1]; locus 6p22) occupies a central position in central nervous system (CNS) neurotransmitter metabolism as one of two enzymes necessary for <it>γ</it>-aminobutyric acid (GAB...
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| Format: | Article |
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BMC
2009-01-01
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| Series: | Human Genomics |
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| Online Access: | http://www.humgenomics.com/content/3/2/106 |
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| author | Malaspina Patrizia Picklo Matthew J Jakobs C Snead O Carter Gibson K Michael |
| author_facet | Malaspina Patrizia Picklo Matthew J Jakobs C Snead O Carter Gibson K Michael |
| author_sort | Malaspina Patrizia |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Succinic semialdehyde dehydrogenase (SSADH; aldehyde dehydrogenase 5A1 [ALDH5A1]; locus 6p22) occupies a central position in central nervous system (CNS) neurotransmitter metabolism as one of two enzymes necessary for <it>γ</it>-aminobutyric acid (GABA) recycling from the synaptic cleft. Its importance is highlighted by the neurometabolic disease associated with its inherited deficiency in humans, as well as the severe epileptic phenotype observed in <it>Aldh5a1</it><sup>-/- </sup>knockout mice. Expanding evidence now suggests, however, that even subtle decreases in human SSADH activity, associated with rare and common single nucleotide polymorphisms, may produce subclinical pathological effects. SSADH, in conjunction with aldo-keto reductase 7A2 (AKR7A2), represent two neural enzymes responsible for further catabolism of succinic semialdehyde, producing either succinate (SSADH) or <it>γ</it>-hydroxybutyrate (GHB; AKR7A2). A GABA analogue, GHB is a short-chain fatty alcohol with unusual properties in the CNS and a long pharmacological history. Moreover, SSADH occupies a further role in the CNS as the enzyme responsible for further metabolism of the lipid peroxidation aldehyde 4-hydroxy-2-nonenal (4-HNE), an intermediate known to induce oxidant stress. Accordingly, subtle decreases in SSADH activity may have the capacity to lead to regional accumulation of neurotoxic intermediates (GHB, 4-HNE). Polymorphisms in SSADH gene structure may also associate with quantitative traits, including intelligence quotient and life expectancy. Further population-based studies of human SSADH activity promise to reveal additional properties of its function and additional roles in CNS tissue.</p> |
| first_indexed | 2024-04-11T13:27:23Z |
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| issn | 1479-7364 |
| language | English |
| last_indexed | 2024-04-11T13:27:23Z |
| publishDate | 2009-01-01 |
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| series | Human Genomics |
| spelling | doaj.art-036703f35410463c8067216c15a78b1c2022-12-22T04:22:00ZengBMCHuman Genomics1479-73642009-01-013210612010.1186/1479-7364-3-2-106Comparative genomics of aldehyde dehydrogenase 5a1 (succinate semialdehyde dehydrogenase) and accumulation of gamma-hydroxybutyrate associated with its deficiencyMalaspina PatriziaPicklo Matthew JJakobs CSnead O CarterGibson K Michael<p>Abstract</p> <p>Succinic semialdehyde dehydrogenase (SSADH; aldehyde dehydrogenase 5A1 [ALDH5A1]; locus 6p22) occupies a central position in central nervous system (CNS) neurotransmitter metabolism as one of two enzymes necessary for <it>γ</it>-aminobutyric acid (GABA) recycling from the synaptic cleft. Its importance is highlighted by the neurometabolic disease associated with its inherited deficiency in humans, as well as the severe epileptic phenotype observed in <it>Aldh5a1</it><sup>-/- </sup>knockout mice. Expanding evidence now suggests, however, that even subtle decreases in human SSADH activity, associated with rare and common single nucleotide polymorphisms, may produce subclinical pathological effects. SSADH, in conjunction with aldo-keto reductase 7A2 (AKR7A2), represent two neural enzymes responsible for further catabolism of succinic semialdehyde, producing either succinate (SSADH) or <it>γ</it>-hydroxybutyrate (GHB; AKR7A2). A GABA analogue, GHB is a short-chain fatty alcohol with unusual properties in the CNS and a long pharmacological history. Moreover, SSADH occupies a further role in the CNS as the enzyme responsible for further metabolism of the lipid peroxidation aldehyde 4-hydroxy-2-nonenal (4-HNE), an intermediate known to induce oxidant stress. Accordingly, subtle decreases in SSADH activity may have the capacity to lead to regional accumulation of neurotoxic intermediates (GHB, 4-HNE). Polymorphisms in SSADH gene structure may also associate with quantitative traits, including intelligence quotient and life expectancy. Further population-based studies of human SSADH activity promise to reveal additional properties of its function and additional roles in CNS tissue.</p>http://www.humgenomics.com/content/3/2/106GABAGHBsuccinic semialdehyde dehydrogenase deficiencyaldehyde dehydrogenase 5A1chromosome 6p22<it>Aldh5a1</it><sup>-/- </sup>mouse modelalternative splicingAKR7A2polymorphic variationquantitative traits |
| spellingShingle | Malaspina Patrizia Picklo Matthew J Jakobs C Snead O Carter Gibson K Michael Comparative genomics of aldehyde dehydrogenase 5a1 (succinate semialdehyde dehydrogenase) and accumulation of gamma-hydroxybutyrate associated with its deficiency Human Genomics GABA GHB succinic semialdehyde dehydrogenase deficiency aldehyde dehydrogenase 5A1 chromosome 6p22 <it>Aldh5a1</it><sup>-/- </sup>mouse model alternative splicing AKR7A2 polymorphic variation quantitative traits |
| title | Comparative genomics of aldehyde dehydrogenase 5a1 (succinate semialdehyde dehydrogenase) and accumulation of gamma-hydroxybutyrate associated with its deficiency |
| title_full | Comparative genomics of aldehyde dehydrogenase 5a1 (succinate semialdehyde dehydrogenase) and accumulation of gamma-hydroxybutyrate associated with its deficiency |
| title_fullStr | Comparative genomics of aldehyde dehydrogenase 5a1 (succinate semialdehyde dehydrogenase) and accumulation of gamma-hydroxybutyrate associated with its deficiency |
| title_full_unstemmed | Comparative genomics of aldehyde dehydrogenase 5a1 (succinate semialdehyde dehydrogenase) and accumulation of gamma-hydroxybutyrate associated with its deficiency |
| title_short | Comparative genomics of aldehyde dehydrogenase 5a1 (succinate semialdehyde dehydrogenase) and accumulation of gamma-hydroxybutyrate associated with its deficiency |
| title_sort | comparative genomics of aldehyde dehydrogenase 5a1 succinate semialdehyde dehydrogenase and accumulation of gamma hydroxybutyrate associated with its deficiency |
| topic | GABA GHB succinic semialdehyde dehydrogenase deficiency aldehyde dehydrogenase 5A1 chromosome 6p22 <it>Aldh5a1</it><sup>-/- </sup>mouse model alternative splicing AKR7A2 polymorphic variation quantitative traits |
| url | http://www.humgenomics.com/content/3/2/106 |
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