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

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 first 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.

SUBMITTER: Schoemans R

PROVIDER: S-EPMC3071566 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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

Schoemans Renaud R Aigrot Marie-Stéphane MS Wu Chaohong C Marée Raphaël R Hong Pengyu P Belachew Shibeshi S Josse Claire C Lubetzki Catherine C Bours Vincent V

Journal of inherited metabolic disease 20100212 2

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 first showed in a mouse model of PKU that the number of oligodendrocytes is not different in corpus callosum sections from adult mutants o ...[more]

PMID: 20151197

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Project description:IntroductionRemyelination of demyelinated axons can occur as an endogenous repair mechanism in multiple sclerosis (MS), but its efficacy varies between both MS individuals and lesions. The molecular and cellular mechanisms that drive remyelination remain poorly understood. Here, we studied the relation between microglia activation and remyelination activity in MS.MethodsWe correlated regenerative (CD163+) and inflammatory (iNOS+) microglia with BCAS1+ oligodendrocytes, subdivided into early-stage (<3 processes) and late-stage (≥3 processes) cells in brain donors with high or low remyelinating potential in remyelinated lesions and active lesions with ramified/amoeboid (non-foamy) or foamy microglia. A cohort of MS donors categorized as efficiently remyelinating donors (ERDs; n=25) or poorly remyelinating donors (PRDs; n=17) was included, based on their proportion of remyelinated lesions at autopsy.Results and discussionWe hypothesized more CD163+ microglia and BCAS1+ oligodendrocytes in remyelinated and active non-foamy lesions from ERDs and more iNOS+ microglia with fewer BCAS1+ oligodendrocytes in active foamy lesions from PRDs. For CD163+ microglia, however, no differences were observed between MS lesions and MS donor groups. In line with our hypothesis, we found that INOS+ microglia were significantly increased in PRDs compared to ERDs within remyelinated lesions. MS lesions, more late-stage BCAS1+ oligodendrocytes were detected in active lesions with non-foamy or foamy microglia in comparison with remyelinated lesions. Although no differences were found for early-stage BCAS1+ oligodendrocytes between MS lesions, we did find significantly more early-stage BCAS1+ oligodendrocytes in PRDs vs ERDs in remyelinated lesions. Interestingly, a positive correlation was identified between iNOS+ microglia and the presence of early-stage BCAS1+ oligodendrocytes. These findings suggest that impaired maturation of early-stage BCAS1+ oligodendrocytes, encountering inflammatory microglia, may underlie remyelination deficits and unsuccessful lesion repair in MS.

Dataset Information

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

Publications

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

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