Phenylbutyrate increases pyruvate dehydrogenase complex activity in cells harboring a variety of defects

Détails

Ressource 1Télécharger: BIB_D30E15EFDFEC.P001.pdf (387.67 [Ko])
Etat: Public
Version: Final published version
ID Serval
serval:BIB_D30E15EFDFEC
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Phenylbutyrate increases pyruvate dehydrogenase complex activity in cells harboring a variety of defects
Périodique
Annals of Clinical and Translational Neurology
Auteur(s)
Ferriero R., Boutron A., Brivet M., Kerr D., Morava E., Rodenburg R.J., Bonafé L., Baumgartner M.R., Anikster Y., Braverman N.E., Brunetti-Pierri N.
ISSN
2328-9503 (Print)
2328-9503 (Electronic)
ISSN-L
2328-9503
Statut éditorial
Publié
Date de publication
2014
Peer-reviewed
Oui
Volume
1
Numéro
7
Pages
462-470
Langue
anglais
Notes
Publication types: Research Articles ; research-article Identifiant PubMed Central: PMC4184775
Résumé
OBJECTIVE: Deficiency of pyruvate dehydrogenase complex (PDHC) is the most common genetic disorder leading to lactic acidosis. PDHC deficiency is genetically heterogenous and most patients have defects in the X-linked E1-α gene but defects in the other components of the complex encoded by PDHB, PDHX, DLAT, DLD genes or in the regulatory enzyme encoded by PDP1 have also been found. Phenylbutyrate enhances PDHC enzymatic activity in vitro and in vivo by increasing the proportion of unphosphorylated enzyme through inhibition of pyruvate dehydrogenase kinases and thus, has potential for therapy of patients with PDHC deficiency. In the present study, we investigated response to phenylbutyrate of multiple cell lines harboring all known gene defects resulting in PDHC deficiency.
METHODS: Fibroblasts of patients with PDHC deficiency were studied for their enzyme activity at baseline and following phenylbutyrate incubation. Drug responses were correlated with genotypes and protein levels by Western blotting.
RESULTS: Large deletions affecting PDHA1 that result in lack of detectable protein were unresponsive to phenylbutyrate, whereas increased PDHC activity was detected in most fibroblasts harboring PDHA1 missense mutations. Mutations affecting the R349-α residue were directed to proteasome degradation and were consistently unresponsive to short-time drug incubation but longer incubation resulted in increased levels of enzyme activity and protein that may be due to an additional effect of phenylbutyrate as a molecular chaperone.
INTERPRETATION: PDHC enzyme activity was enhanced by phenylbutyrate in cells harboring missense mutations in PDHB, PDHX, DLAT, DLD, and PDP1 genes. In the prospect of a clinical trial, the results of this study may allow prediction of in vivo response in patients with PDHC deficiency harboring a wide spectrum of molecular defects.
Pubmed
Open Access
Oui
Création de la notice
11/07/2016 11:04
Dernière modification de la notice
20/08/2019 16:53
Données d'usage