Phenylbutyrate increases pyruvate dehydrogenase complex activity in cells harboring a variety of defects. (19th June 2014)

• Record Type: Journal Article
• Authors: Ferriero, Rosa; Boutron, Audrey; Brivet, Michele; Kerr, Douglas; Morava, Eva; Rodenburg, Richard J.; Bonafé, Luisa; Baumgartner, Matthias R.; Anikster, Yair; Braverman, Nancy E.; Brunetti‐Pierri, Nicola
• Is Part Of: Annals of clinical and translational neurology. Volume 1:Number 7(2014)
• Page Start: 462
• Page End: 470
• Publication Date: 2014-06-19
• Subjects: Nervous system -- Diseases -- Periodicals; Neurology -- Periodicals; 616.8005
• DOI: 10.1002/acn3.73
• Languages: English
• ISSNs: 2328-9503

Abstract

<abstract abstract-type="main" id="acn373-abs-0001"> <title>Abstract</title> <sec id="acn373-sec-0001" sec-type="section"> <title>Objective</title> <p>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‐<italic>α</italic> gene but defects in the other components of the complex encoded by <italic>PDHB</italic>, <italic> PDHX</italic>, <italic> DLAT</italic>, <italic> DLD</italic> genes or in the regulatory enzyme encoded by <italic>PDP1</italic> 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.</p> </sec> <sec id="acn373-sec-0002" sec-type="section"> <title>Methods</title> <p>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.</p> </sec> <sec id="acn373-sec-0003" sec-type="section"> <title>Results</title> <p>Large deletions affecting <italic>PDHA1</italic> that result in lack of detectable protein were unresponsive to phenylbutyrate, whereas increased PDHC activity was detected in most fibroblasts harboring <italic>PDHA1</italic> missense mutations. Mutations affecting the R349‐<italic>α</italic> 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.</p> </sec> <sec id="acn373-sec-0004" sec-type="section"> <title>Interpretation</title> <p>PDHC enzyme activity was enhanced by phenylbutyrate in cells harboring missense mutations in <italic>PDHB</italic>, <italic> PDHX</italic>, <italic> DLAT</italic>, <italic> DLD</italic>, and <italic>PDP1</italic> 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.</p> </sec> </abstract>