Multifactorial modulation of susceptibility to l-lysine in an animal model of glutaric aciduria type I

Sven W. Sauer, Silvana Opp, Shoko Komatsuzaki, Anna Eva Blank, Michel Mittelbronn, Peter Burgard, David Koeller, Jürgen G. Okun, Stefan Kölker

Research output: Contribution to journalArticle

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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. 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.

Original languageEnglish (US)
Pages (from-to)768-777
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1852
Issue number5
DOIs
StatePublished - May 1 2015

Fingerprint

Lysine
Animal Models
Corpus Striatum
Hydroxylysine
Ketoglutarate Dehydrogenase Complex
Aconitate Hydratase
Diet
Glutaric Acidemia I
Glyceraldehyde-3-Phosphate Dehydrogenases
Inbreeding
Poisons
Cerebral Hemorrhage
Tryptophan
Hippocampus
Eating
glutaric acid
Pathology
Phenotype
Mortality
Wounds and Injuries

Keywords

  • Amino acid
  • Animal model
  • Inborn errors of metabolism
  • Neural metabolism
  • Neurodegenerative disease

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Medicine(all)

Cite this

Multifactorial modulation of susceptibility to l-lysine in an animal model of glutaric aciduria type I. / Sauer, Sven W.; Opp, Silvana; Komatsuzaki, Shoko; Blank, Anna Eva; Mittelbronn, Michel; Burgard, Peter; Koeller, David; Okun, Jürgen G.; Kölker, Stefan.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1852, No. 5, 01.05.2015, p. 768-777.

Research output: Contribution to journalArticle

Sauer, Sven W. ; Opp, Silvana ; Komatsuzaki, Shoko ; Blank, Anna Eva ; Mittelbronn, Michel ; Burgard, Peter ; Koeller, David ; Okun, Jürgen G. ; Kölker, Stefan. / Multifactorial modulation of susceptibility to l-lysine in an animal model of glutaric aciduria type I. In: Biochimica et Biophysica Acta - Molecular Basis of Disease. 2015 ; Vol. 1852, No. 5. pp. 768-777.
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AU - Koeller, David

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