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Biagosch, C. ; Ediga, R.* ; Hensler, S. ; Faerberboeck, M. ; Kühn, R. ; Wurst, W. ; Meitinger, T. ; Kölker, S.* ; Sauer, S.* ; Prokisch, H.

Elevated glutaric acid levels in Dhtkd1-/Gcdh- double knockout mice challenge our current understanding of lysine metabolism.

Biochim. Biophys. Acta 1863, 2220-2228 (2017)
Open Access Green as soon as Postprint is submitted to ZB.
Glutaric aciduria type I (GA-I) is a rare organic aciduria caused by the autosomal recessive inherited deficiency of glutaryl-CoA dehydrogenase (GCDH). GCDH deficiency leads to disruption of L-lysine degradation with characteristic accumulation of glutarylcarnitine and neurotoxic glutaric acid (GA), glutaryl-CoA, 3-hydroxyglutaric acid (3-OHGA). DHTKD1 acts upstream of GCDH, and its deficiency leads to none or often mild clinical phenotype in humans, 2-aminoadipic 2-oxoadipic aciduria. We hypothesized that inhibition of DHTKD1 may prevent the accumulation of neurotoxic dicarboxylic metabolites suggesting DHTKD1 inhibition as a possible treatment strategy for GA-I. In order to validate this hypothesis we took advantage of an existing GA-I (Gcdh(-/-)) mouse model and established a Dhtkd1 deficient mouse model. Both models reproduced the biochemical and clinical phenotype observed in patients. Under challenging conditions of a high lysine diet, only Gcdh(-/-) mice but not Dhtkd1(-/-) mice developed clinical symptoms such as lethargic behaviour and weight loss. However, the genetic Dhtkd1 inhibition in Dhtkd1(-/-)/Gcdh(-/-) mice could not rescue the GA-I phenotype. Biochemical results confirm this finding with double knockout mice showing similar metabolite accumulations as Gcdh(-/-) mice with high GA in brain and liver. This suggests that DHTKD1 inhibition alone is not sufficient to treat GA-I, but instead a more complex strategy is needed. Our data highlights the many unresolved questions within the L-lysine degradation pathway and provides evidence for a so far unknown mechanism leading to glutaryl-CoA.
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Publication type Article: Journal article
Document type Scientific Article
Keywords 2-aminoadipic 2-oxoadipic Aciduria ; Dhtkd1 ; Gcdh ; Glutaric Aciduria Type I ; L-lysine ; Glutaric Acid; Coa Dehydrogenase-deficiency; Blood-brain-barrier; Alpha-ketoadipic Aciduria; L-pipecolate Oxidase; 2-oxoglutarate Dehydrogenase; Natural-history; Mouse Model; Type-1; Phenotype; Neurodegeneration
ISSN (print) / ISBN 0006-3002
Quellenangaben Volume: 1863, Issue: 9, Pages: 2220-2228 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place Amsterdam