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

Schumacher U, Lukacs Z, Kaltschmidt C, et al. High concentrations of phenylalanine stimulate peroxisome proliferator-activated receptor gamma: Implications for the pathophysiology of phenylketonuria. NEUROBIOLOGY OF DISEASE. 2008;32(3):385-390.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 PPAR gamma 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 PPAR gamma 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. (C) 2008 Elsevier Inc. All rights reserved