Multifactorial modulation of susceptibility to l-lysine in an animal model of glutaric aciduria type I
Glutaric aciduria type I is an inherited defect in l-lysine, l-hydroxylysine and l-tryptophan degradation caused by deficiency of glutaryl-CoA dehydrogenase (GCDH). The majority of untreated patients presents with accumulation of neurotoxic metabolites - glutaric acid (GA) and 3-hydroxyglutaric acid...
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| Hauptverfasser: | , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
2 January 2015
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| In: |
Biochimica et biophysica acta. Molecular basis of disease
Year: 2015, Jahrgang: 1852, Heft: 5, Pages: 768-777 |
| ISSN: | 1879-260X |
| DOI: | 10.1016/j.bbadis.2014.12.022 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1016/j.bbadis.2014.12.022 Verlag, kostenfrei, Volltext: http://www.sciencedirect.com/science/article/pii/S0925443914004165 
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| Verfasserangaben: | Sven W. Sauer, Silvana Opp, Shoko Komatsuzaki, Anna-Eva Blank, Michel Mittelbronn, Peter Burgard, D.M. Koeller, Jürgen G. Okun, Stefan Kölker |
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| 245 | 1 | 0 | |a Multifactorial modulation of susceptibility to l-lysine in an animal model of glutaric aciduria type I |c Sven W. Sauer, Silvana Opp, Shoko Komatsuzaki, Anna-Eva Blank, Michel Mittelbronn, Peter Burgard, D.M. Koeller, Jürgen G. Okun, Stefan Kölker |
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| 520 | |a Glutaric aciduria type I is an inherited defect in l-lysine, l-hydroxylysine and l-tryptophan degradation caused by deficiency of glutaryl-CoA dehydrogenase (GCDH). The majority of untreated patients presents with accumulation of neurotoxic metabolites - glutaric acid (GA) and 3-hydroxyglutaric acid (3-OHGA) - and striatal injury. Gcdh−/− mice display elevated levels of GA and 3-OH-GA but do not spontaneously develop striatal lesions. l-lysine-enriched diets (appr. 235mg/d) were suggested to induce a neurological phenotype similar to affected patients. In our hands 93% of mice stressed according to the published protocol remained asymptomatic. To understand the underlying mechanism, we modified their genetic background (F1 C57BL6/Jx129/SvCrl) and increased the daily oral l-lysine supply (235-433mg). We identified three modulating factors, (1) gender, (2) genetic background, and (3) amount of l-lysine. Male mice displayed higher vulnerability and inbreeding for more than two generations as well as elevating l-lysine supply increased the diet-induced mortality rate (up to 89%). Onset of first symptoms leads to strongly reduced intake of food and, thus, l-lysine suggesting a threshold for toxic metabolite production to induce neurological disease. GA and 3-OH-GA tissue concentrations did not correlate with dietary l-lysine supply but differed between symptomatic and asymptomatic mice. Cerebral activities of glyceraldehyde 3-phosphate dehydrogenase, 2-oxoglutarate dehydrogenase complex, and aconitase were decreased. Symptomatic mice did not develop striatal lesions or intracerebral hemorrhages. We found severe spongiosis in the hippocampus of Gcdh−/− mice which was independent of dietary l-lysine supply. In conclusion, the l-lysine-induced pathology in Gcdh−/− mice depends on genetic and dietary parameters. | ||
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| 650 | 4 | |a Animal model | |
| 650 | 4 | |a Inborn errors of metabolism | |
| 650 | 4 | |a Neural metabolism | |
| 650 | 4 | |a Neurodegenerative disease | |
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