3‐Ureidopropionate contributes to the neuropathology of 3‐ureidopropionase deficiency and severe propionic aciduria: A hypothesis

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 α‐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 β‐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. J. Neurosci. Res. 66:666–673, 2001. © 2001 Wiley‐Liss, Inc.