High concentrations of phenylalanine stimulate peroxisome proliferator-activated receptor γ: Implications for the pathophysiology of phenylketonuria

Udo Schumacher, Zoltan Lukacs, Christian Kaltschmidt, Christian Freudlsperger, Dorothea Schulz, Kai Kompisch, Reinhard Müller, Tanja Rudolph, René Santer, Dietrich E. Lorke, Kurt Ullrich

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

If left untreated, the common inherited metabolic disorder phenylketonuria (PKU) presents with mental retardation and reduced brain weight. The underlying molecular reasons for these deficits are unknown so far. Using human neuroblastoma cells as a model for normal human neuroblasts, elevated phenylalanine concentrations suppressed proliferation of these cells in culture. Furthermore, microarray and functional assays of these cells revealed that both phenylalanine and the known PPARγ agonist rosiglitazone regulated the same set of genes causing subsequently similar changes in the functional assays. The lowered brain weight of PKU patients may thus be the result of reduced neuroblast proliferation caused by phenylalanine-induced stimulation of PPARγ receptors. The observation that high concentrations of small substrates can activate receptors may serve as a new paradigm for other metabolic diseases and provides a new approach for the treatment of these disorders by application of specific receptor antagonists.

Original languageBritish English
Pages (from-to)385-390
Number of pages6
JournalNeurobiology of Disease
Volume32
Issue number3
DOIs
StatePublished - Dec 2008

Keywords

  • Neuroblastoma cells
  • Pathophysiology
  • Peroxisome proliferator-activated receptor gamma
  • Phenylketonuria

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