Oligodendrocyte development and myelinogenesis are not impaired by high concentrations of phenylalanine or its metabolites
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Phenylketonuria (PKU) is a metabolic genetic disease characterized by deficient phenylalanine hydroxylase (PAH) enzymatic activity. Brain hypomyelination has been reported in untreated patients, but its mechanism remains unclear. We therefore investigated the influence of phenylalanine (Phe), phenylpyruvate (PP), and phenylacetate (PA) on oligodendrocytes. We fisrt showed in a mouse model of PKU that the number of oligodendrocytes is not different in corpus callosum sections from adult mutants or from control brains. Then, using enriched oligodendroglial cultures, we detected no cytotoxic effect of high concentrations of Phe, PP, or PA. Finally, we analyzed the impact of Phe, PP, and PA on the myelination process in myelinating cocultures using both an in vitro index of myelination, based on activation of the myelin basic protein (MBP) promoter, and the direct quantification of myelin sheaths by both optical measurement and a bioinformatics method. None of these parameters was affected by the increased levels of Phe or its derivatives. Taken together, our data demonstrate that high levels of Phe, such as in PKU, are unlikely to directly induce brain hypomyelination, suggesting involvement of alternative mechanisms in this myelination defect.
KeywordsCorpus Callosum Myelin Basic Protein Myelin Sheath Large Neutral Amino Acid Oligodendrocyte Development
List of abbreviations
Large neutral amino acids
Oligodendrocyte progenitor cells
The authors thank the Imaging Platform, the SPF Animal Facility, and the Neurosciences Department from GIGA-Research for their experimental help. We also thank Olympus Belgium N.V. for providing the Cell^R system.
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