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Oligodendrocyte development and myelinogenesis are not impaired by high concentrations of phenylalanine or its metabolites

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

Abstract

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.

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Abbreviations

PKU:

Phenylketonuria

PAH:

Phenylalanine hydroxylase

Phe:

Phenylalanine

Tyr:

Tyrosine

PP:

Phenylpyruvate

PA:

Phenylacetate

LNAA:

Large neutral amino acids

OPC:

Oligodendrocyte progenitor cells

SVZ:

Subventricular zone

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Acknowledgments

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.

Competing interest

None declared.

Author information

Authors and Affiliations

  1. Human Genetics, GIGA-Research, University of Liège, Liège, Belgium

    Renaud Schoemans, Claire Josse & Vincent Bours

  2. Cr-Icm, Inserm 711, UPMC, Paris, France

    Marie-Stéphane Aigrot & Catherine Lubetzki

  3. Michtom School of Computer Science, Volen Center for Complex Systems, Room 261, Brandeis University, Waltham, MA, 02454, USA

    Chaohong Wu & Pengyu Hong

  4. Bioinformatics platform, GIGA-Research, University of Liège, Liège, Belgium

    Raphaël Marée

  5. Neurosciences, GIGA-Research, University of Liège, Liège, Belgium

    Shibeshi Belachew

  6. Genetics Center, CHU Liège, Liège, Belgium

    Vincent Bours

  7. Department of Genetics, CHU Liège, Université de Liège B34, Avenue de l’hôpital 1, 4000, Liège, Belgique, Belgium

    Vincent Bours

Authors
  1. Renaud Schoemans
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  2. Marie-Stéphane Aigrot
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  3. Chaohong Wu
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  4. Raphaël Marée
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  6. Shibeshi Belachew
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  7. Claire Josse
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  8. Catherine Lubetzki
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  9. Vincent Bours
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Correspondence to Vincent Bours.

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Communicated by: Bruce A. Barshop

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Schoemans, R., Aigrot, MS., Wu, C. et al. Oligodendrocyte development and myelinogenesis are not impaired by high concentrations of phenylalanine or its metabolites. J Inherit Metab Dis 33, 113–120 (2010). https://doi.org/10.1007/s10545-010-9052-3

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  • DOI: https://doi.org/10.1007/s10545-010-9052-3

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