title: Multifactorial modulation of susceptibility to l-lysine in an animal model of glutaric aciduria type I.
abstract: 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. 235 mg/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 (235-433 mg). 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.
authors.affiliation: Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Children's Hospital Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Sven W
authors.initials: SW
authors.lastname: Sauer
authors.affiliation: Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Children's Hospital Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Silvana
authors.initials: S
authors.lastname: Opp
authors.affiliation: Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Children's Hospital Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Shoko
authors.initials: S
authors.lastname: Komatsuzaki
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe-University Frankfurt, D-60528 Frankfurt/Main, Germany.
authors.forename: Anna-Eva
authors.initials: AE
authors.lastname: Blank
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe-University Frankfurt, D-60528 Frankfurt/Main, Germany.
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.affiliation: Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Children's Hospital Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Burgard
authors.affiliation: Department of Pediatrics, Oregon Health and Science University, Portland, OR, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Koeller
authors.affiliation: Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Children's Hospital Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Jürgen G
authors.initials: JG
authors.lastname: Okun
authors.affiliation: Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Children's Hospital Heidelberg, D-69120 Heidelberg, Germany. Electronic address: stefan.koelker@med.uni-heidelberg.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kölker
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000592:Amino Acid Metabolism, Inborn Errors / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001928:Brain Diseases, Metabolic / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D004032:Diet; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D020022:Genetic Predisposition to Disease / Q000209:etiology / Q000235:genetics*; D005977:Glutarates / Q000378:metabolism; D050770:Glutaryl-CoA Dehydrogenase / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism; D008239:Lysine / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012307:Risk Factors; D012737:Sex Factors; D013053:Spectrophotometry
chemical_list: C108959:3-hydroxyglutaric acid; D005977:Glutarates; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D007655:Ketoglutarate Dehydrogenase Complex; D050770:Glutaryl-CoA Dehydrogenase; D000154:Aconitate Hydratase; C035736:glutaric acid; D008239:Lysine
keywords: Amino acid; Animal model; Inborn errors of metabolism; Neural metabolism; Neurodegenerative disease