Glutaric acidemia type I (GA-I) is a neurometabolic disease caused by deficient activity of glutaryl-CoA dehydrogenase (GCDH) that results in accumulation of metabolites derived from lysine (Lys), hydroxylysine, and tryptophan catabolism. GA-I patients typically develop encephalopatic crises with striatal degeneration and progressive white matter defects. However, late onset patients as well as Gcdh-/- mice only suffer diffuse myelinopathy, suggesting that neuronal death and white matter defects are different pathophysiological events. To test this hypothesis, striatal myelin was studied in Gcdh-/- mice fed from 30 days of age during up to 60 days with a diet containing normal or moderately increased amounts of Lys (2.8%), which ensure sustained elevated levels of GA-I metabolites. Gcdh-/- mice fed with 2.8% Lys diet showed a significant decrease in striatal-myelinated areas and progressive vacuolation of white matter tracts, as compared with animals fed with normal diet. Myelin pathology increased with the time of exposure to high Lys diet and was also detected in 90-day old Gcdh-/- mice fed with normal diet, suggesting that dietary Lys accelerated the undergoing white matter damage. Gcdh-/- mice fed with 2.8% Lys diet also showed increased GRP78/BiP immunoreactivity in oligodendrocytes and neurons, denoting ER stress. However, the striatal and cortical neuronal density was unchanged with respect to normal diet. Thus, myelin damage seen in Gcdh-/- mice fed with 2.8% Lys seems to be mediated by a long-term increased levels of GA-I metabolites having deleterious effects in myelinating oligodendrocytes over neurons.
Keywords: Gcdh−/− mice; Glutaric acidemia type I; Lysine overdose; Myelin alterations.