title: 3-Ureidopropionate contributes to the neuropathology of 3-ureidopropionase deficiency and severe propionic aciduria: a hypothesis.
abstract: 3-Ureidopropionate (3-UPA) is a physiologic metabolite in pyrimidine degradation. Pathological accumulation of 3-UPA in body fluids is found in 3-ureidopropionase deficiency and severe forms of propionic aciduria. Both diseases clinically present with a severe neuropathology involving gray and white matter as well as with a dystonic dyskinetic movement disorder. To date nothing is known about the toxic nature of this metabolite. The aim of the present study was to elucidate whether 3-UPA may act as endogenous neurotoxin. Exposure of cultured chick neurons to 3-UPA induced a concentration- and time-dependent neurodegeneration. Neuronal damage was reduced by the antioxidant alpha-tocopherol and the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801. In contrast, the non-NMDA receptor antagonist CNQX, the metabotropic glutamate receptor antagonist L-AP3, and succinate showed no protective effect. Furthermore, 3-UPA elicited an increased production of reactive oxygen species followed by a delayed increase in intracellular calcium concentrations. Activity measurement of single respiratory chain complexes I-V revealed an inhibition of complex V activity, but not of the electron-transferring complexes I-IV by 3-UPA. In contrast, 3-UPA did not affect the mitochondrial beta-oxidation of fatty acids. In conclusion, our results provide strong evidence that 3-UPA acts as endogenous neurotoxin via inhibition of mitochondrial energy metabolism, resulting in the initiation of secondary, energy-dependent excitotoxic mechanisms.
authors.affiliation: Division of Metabolic and Endocrine Diseases, University Children's Hospital, Heidelberg, Germany. Stefan_Koelker@med.uni-heidelberg.de
authors.forename: S
authors.initials: S
authors.lastname: Kölker
authors.forename: J G
authors.initials: JG
authors.lastname: Okun
authors.forename: F
authors.initials: F
authors.lastname: Hörster
authors.forename: B
authors.initials: B
authors.lastname: Assmann
authors.forename: B
authors.initials: B
authors.lastname: Ahlemeyer
authors.forename: D
authors.initials: D
authors.lastname: Kohlmüller
authors.forename: S
authors.initials: S
authors.lastname: Exner-Camps
authors.forename: E
authors.initials: E
authors.lastname: Mayatepek
authors.forename: J
authors.initials: J
authors.lastname: Krieglstein
authors.forename: G F
authors.initials: GF
authors.lastname: Hoffmann
mesh_terms: D000818:Animals; D001928:Brain Diseases, Metabolic / Q000378:metabolism* / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism* / Q000503:physiopathology; D002642:Chick Embryo; D002956:Citrulline / Q000494:pharmacology; D004579:Electron Transport / Q000187:drug effects / Q000502:physiology; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005559:Formamides / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism* / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology*; D011422:Propionates / Q000633:toxicity / Q000652:urine*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D014508:Urea / Q000494:pharmacology; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000172:deficiency* / Q000633:toxicity
chemical_list: D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D005559:Formamides; D009498:Neurotoxins; D011422:Propionates; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; D015091:beta-Alanine; D002956:Citrulline; D018698:Glutamic Acid; C035122:N-carbamoyl-beta-alanine; D014508:Urea; D002118:Calcium