Phenylbutyrate therapy for pyruvate dehydrogenase deficiency

Détails

ID Serval
serval:BIB_D25256CD5075
Type
Actes de conférence (partie): contribution originale à la littérature scientifique, publiée à l'occasion de conférences scientifiques, dans un ouvrage de compte-rendu (proceedings), ou dans l'édition spéciale d'un journal reconnu (conference proceedings).
Sous-type
Abstract (résumé de présentation): article court qui reprend les éléments essentiels présentés à l'occasion d'une conférence scientifique dans un poster ou lors d'une intervention orale.
Collection
Publications
Titre
Phenylbutyrate therapy for pyruvate dehydrogenase deficiency
Titre de la conférence
12th International Congress of Human Genetics
Auteur(s)
Ferriero Rosa, Lamantea Eleonora, Nusco Edoardo, Bonafe Luisa, Lee Brendan, Zeviani Massimo, Brunetti-Pierri Nicola
Adresse
Oct 11-15, 2011; Montréal, Canada
ISBN
1567-7249
ISSN-L
1567-7249
Statut éditorial
Publié
Date de publication
2012
Volume
12
Série
Mitochondrion
Pages
572-573
Langue
anglais
Résumé
Deficiency of pyruvate dehydrogenase complex (PDHC) is the most common disorder leading to lactic acidemia. Phosphorylation of specific serine residues of the E1-alpha subunit of the PDHC by pyruvate dehydrogenase kinase (PDK) inactivates the enzyme, whereas dephosphorylation restores PDHC activity. We recently found that phenylbutyrate prevents phosphorylation of the E1-alpha subunit of the branched-chain ketoacid dehydrogenase complex (BCKDC) and reduces plasma concentrations of neurotoxic branched chain amino acids in patients with maple syrup urine disease (MSUD), due to the deficiency of BCKDC. We hypothesized that, similarly to BCKDC, phenylbutyrate enhances PDHC enzymatic activity by increasing the portion of unphosphorylated enzyme. To test this hypothesis, we treated wild-type human fibroblasts at different concentrations of phenylbutyrate and found that it reduces the levels of phosphorylated E1-alpha as compared to untreated cells. To investigate the effect of phenylbutyrate in vivo, we administered phenylbutyrate to C57B6 wild-type mice and we detected a significant increase in Pdhc enzyme activity and a reduction of phosphorylated E1-alpha subunit in brains and muscles as compared to saline treated mice. Being a drug already approved for human use, phenylbutyrate has great potential for increasing the residual enzymatic activity of PDHC and to improve the clinical phenotype of PDHC deficiency.
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Création de la notice
17/12/2012 12:02
Dernière modification de la notice
20/08/2019 15:52
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