Temporal metabolomics in dried bloodspots suggests multipathway disruptions in aldh5a1-/- mice, a model of succinic semialdehyde dehydrogenase deficiency.
Mol Genet Metab
; 128(4): 397-408, 2019 12.
Article
em En
| MEDLINE
| ID: mdl-31699650
ABSTRACT
Succinic semialdehyde dehydrogenase (SSADH) deficiency (SSADHD; OMIM 271980) is a rare disorder featuring accumulation of neuroactive 4-aminobutyric acid (GABA; γ-aminobutyric acid, derived from glutamic acid) and 4-hydroxybutyric acid (γ-hydroxybutyric acid; GHB, a short-chain fatty acid analogue of GABA). Elevated GABA is predicted to disrupt the GABA shunt linking GABA transamination to the Krebs cycle and maintaining the balance of excitatoryinhibitory neurotransmitters. Similarly, GHB (or a metabolite) is predicted to impact ß-oxidation flux. We explored these possibilities employing temporal metabolomics of dried bloodspots (DBS), quantifying amino acids, acylcarnitines, and guanidino- metabolites, derived from aldh5a1+/+, aldh5a1+/- and aldh5a1-/- mice (aldehyde dehydrogenase 5a1â¯=â¯SSADH) at day of life (DOL) 20 and 42â¯days. At DOL 20, aldh5a1-/- mice had elevated C6 dicarboxylic (adipic acid) and C14 carnitines and threonine, combined with a significantly elevated ratio of threonine/[aspartic acid + alanine], in comparison to aldh5a1+/+ mice. Conversely, at DOL 42 aldh5a1-/- mice manifested decreased short chain carnitines (C0-C6), valine and glutamine, in comparison to aldh5a1+/+ mice. Guanidino species, including creatinine, creatine and guanidinoacetic acid, evolved from normal levels (DOL 20) to significantly decreased values at DOL 42 in aldh5a1-/- as compared to aldh5a1+/+ mice. Our results provide a novel temporal snapshot of the evolving metabolic profile of aldh5a1-/- mice while highlighting new pathomechanisms in SSADHD.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Biomarcadores
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Deficiências do Desenvolvimento
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Succinato-Semialdeído Desidrogenase
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Redes e Vias Metabólicas
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Metabolômica
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Erros Inatos do Metabolismo dos Aminoácidos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article