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| Item Type: | Article |
|---|---|
| Title: | Elevated glutaric acid levels in Dhtkd1-/Gcdh- double knockout mice challenge our current understanding of lysine metabolism |
| Creators Name: | Biagosch, C., Ediga, R.D., Hensler, S.V., Faerberboeck, M., Kuehn, R., Wurst, W., Meitinger, T., Kölker, S., Sauer, S. and Prokisch, H. |
| Abstract: | 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. |
| Keywords: | Glutaric Aciduria Type I, 2-Aminoadipic 2-Oxoadipic Aciduria, L-Lysine, GCDH, DHTKD1, Glutaric Acid, Animals, Mice |
| Source: | Biochimica et Biophysica Acta - Molecular Basis of Disease |
| ISSN: | 0925-4439 |
| Publisher: | Elsevier |
| Volume: | 1863 |
| Number: | 9 |
| Page Range: | 2220-2228 |
| Date: | September 2017 |
| Official Publication: | https://doi.org/10.1016/j.bbadis.2017.05.018 |
| PubMed: | View item in PubMed |
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