Elevated glutaric acid levels in Dhtkd1-/Gcdh- double knockout mice challenge our current understanding of lysine metabolism
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),...
Gespeichert in:
| Hauptverfasser: | , , |
|---|---|
| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
2017
|
| In: |
Biochimica et biophysica acta. Molecular basis of disease
Year: 2017, Jahrgang: 1863, Heft: 9, Pages: 2220-2228 |
| ISSN: | 1879-260X |
| DOI: | 10.1016/j.bbadis.2017.05.018 |
| Online-Zugang: | Verlag, Volltext: http://dx.doi.org/10.1016/j.bbadis.2017.05.018 Verlag, Volltext: http://www.sciencedirect.com/science/article/pii/S0925443917301552 
|
| Verfasserangaben: | Caroline Biagosch, Raga Deepthi Ediga, Svenja-Viola Hensler, Michael Faerberboeck, Ralf Kuehn, Wolfgang Wurst, Thomas Meitinger, Stefan Kölker, Sven Sauer, Holger Prokisch |
MARC
| LEADER | 00000caa a2200000 c 4500 | ||
|---|---|---|---|
| 001 | 1576719707 | ||
| 003 | DE-627 | ||
| 005 | 20220814171306.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 180621s2017 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.bbadis.2017.05.018 |2 doi | |
| 035 | |a (DE-627)1576719707 | ||
| 035 | |a (DE-576)506719707 | ||
| 035 | |a (DE-599)BSZ506719707 | ||
| 035 | |a (OCoLC)1341012095 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rda | ||
| 041 | |a eng | ||
| 084 | |a 33 |2 sdnb | ||
| 100 | 1 | |a Biagosch, Caroline |e VerfasserIn |0 (DE-588)1161555188 |0 (DE-627)1024832848 |0 (DE-576)506719448 |4 aut | |
| 245 | 1 | 0 | |a Elevated glutaric acid levels in Dhtkd1-/Gcdh- double knockout mice challenge our current understanding of lysine metabolism |c Caroline Biagosch, Raga Deepthi Ediga, Svenja-Viola Hensler, Michael Faerberboeck, Ralf Kuehn, Wolfgang Wurst, Thomas Meitinger, Stefan Kölker, Sven Sauer, Holger Prokisch |
| 264 | 1 | |c 2017 | |
| 300 | |a 9 | ||
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Available online 22 May 2017 | ||
| 500 | |a Gesehen am 21.06.2018 | ||
| 520 | |a 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. | ||
| 650 | 4 | |a -lysine | |
| 650 | 4 | |a 2-aminoadipic 2-oxoadipic aciduria | |
| 650 | 4 | |a DHTKD1 | |
| 650 | 4 | |a GCDH | |
| 650 | 4 | |a glutaric acid | |
| 650 | 4 | |a Glutaric aciduria type I | |
| 700 | 1 | |a Kölker, Stefan |e VerfasserIn |0 (DE-588)1022937758 |0 (DE-627)717335771 |0 (DE-576)366197568 |4 aut | |
| 700 | 1 | |a Sauer, Sven |d 1977- |e VerfasserIn |0 (DE-588)1035823713 |0 (DE-627)749614587 |0 (DE-576)383583500 |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Biochimica et biophysica acta. Molecular basis of disease |d Amsterdam : Elsevier, 1990 |g 1863(2017), 9, Seite 2220-2228 |h Online-Ressource |w (DE-627)502924330 |w (DE-600)2209528-7 |w (DE-576)251822699 |x 1879-260X |7 nnas |a Elevated glutaric acid levels in Dhtkd1-/Gcdh- double knockout mice challenge our current understanding of lysine metabolism |
| 773 | 1 | 8 | |g volume:1863 |g year:2017 |g number:9 |g pages:2220-2228 |g extent:9 |a Elevated glutaric acid levels in Dhtkd1-/Gcdh- double knockout mice challenge our current understanding of lysine metabolism |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.bbadis.2017.05.018 |x Verlag |x Resolving-System |3 Volltext |
| 856 | 4 | 0 | |u http://www.sciencedirect.com/science/article/pii/S0925443917301552 |x Verlag |3 Volltext |
| 951 | |a AR | ||
| 992 | |a 20180621 | ||
| 993 | |a Article | ||
| 994 | |a 2017 | ||
| 998 | |g 1035823713 |a Sauer, Sven |m 1035823713:Sauer, Sven |d 910000 |d 910500 |e 910000PS1035823713 |e 910500PS1035823713 |k 0/910000/ |k 1/910000/910500/ |p 9 | ||
| 998 | |g 1022937758 |a Kölker, Stefan |m 1022937758:Kölker, Stefan |d 910000 |d 910500 |e 910000PK1022937758 |e 910500PK1022937758 |k 0/910000/ |k 1/910000/910500/ |p 8 | ||
| 999 | |a KXP-PPN1576719707 |e 3013303786 | ||
| BIB | |a Y | ||
| SER | |a journal | ||
| JSO | |a {"relHost":[{"recId":"502924330","disp":"Elevated glutaric acid levels in Dhtkd1-/Gcdh- double knockout mice challenge our current understanding of lysine metabolismBiochimica et biophysica acta. Molecular basis of disease","origin":[{"publisherPlace":"Amsterdam","dateIssuedKey":"1990","publisher":"Elsevier","dateIssuedDisp":"1990-"}],"id":{"eki":["502924330"],"issn":["1879-260X"],"zdb":["2209528-7"]},"part":{"issue":"9","year":"2017","text":"1863(2017), 9, Seite 2220-2228","extent":"9","pages":"2220-2228","volume":"1863"},"note":["Gesehen am 08.01.2020","Bis 2016 Bände zugleich Bände von: Biochimica et biophysica acta"],"titleAlt":[{"title":"Biochimica et biophysica acta / Molecular basis of disease"}],"type":{"bibl":"periodical","media":"Online-Ressource"},"pubHistory":["1096.1990/91 -"],"physDesc":[{"extent":"Online-Ressource"}],"language":["eng"],"title":[{"title_sort":"Biochimica et biophysica acta","title":"Biochimica et biophysica acta","subtitle":"BBA","partname":"Molecular basis of disease"}]}],"note":["Available online 22 May 2017","Gesehen am 21.06.2018"],"recId":"1576719707","name":{"displayForm":["Caroline Biagosch, Raga Deepthi Ediga, Svenja-Viola Hensler, Michael Faerberboeck, Ralf Kuehn, Wolfgang Wurst, Thomas Meitinger, Stefan Kölker, Sven Sauer, Holger Prokisch"]},"origin":[{"dateIssuedKey":"2017","dateIssuedDisp":"2017"}],"id":{"eki":["1576719707"],"doi":["10.1016/j.bbadis.2017.05.018"]},"type":{"media":"Online-Ressource","bibl":"article-journal"},"language":["eng"],"physDesc":[{"extent":"9 S."}],"title":[{"title":"Elevated glutaric acid levels in Dhtkd1-/Gcdh- double knockout mice challenge our current understanding of lysine metabolism","title_sort":"Elevated glutaric acid levels in Dhtkd1-/Gcdh- double knockout mice challenge our current understanding of lysine metabolism"}],"person":[{"display":"Biagosch, Caroline","role":"aut","given":"Caroline","family":"Biagosch"},{"role":"aut","given":"Stefan","family":"Kölker","display":"Kölker, Stefan"},{"given":"Sven","role":"aut","family":"Sauer","display":"Sauer, Sven"}]} | ||
| SRT | |a BIAGOSCHCAELEVATEDGL2017 | ||