Chemical chaperones improve peroxisomal biogenesis in fibroblasts of mild Zellweger syndrome spectrum patients

Abstract

s ingediend voor het Amsterdam Kindersymposium 2013 21 Chemical chaperones improve peroxisomal biogenesis in fibroblasts of mild Zellweger syndrome spectrum patients Kevin Bere ndse (1,2), Merel S. Ebberink (1), Lodewijk IJlst (1), Bwee Tien Poll-The (2), Ronald J.A. Wanders(1), Hans R. Waterham (1) (1) Laboratory Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, the Netherlands (2) Department of Paediatric Neurology, Emma Children’s Hospital, Academic Medical Center, Amsterdam, the Netherlands INTRODUCTION Zellweger syndrome spectrum (ZSS) disorders are multisystem genetic disorders which lack functional peroxisomes due to a defect in one of the PEX genes. The ZSS include three phenotypes, which represent a spectrum of disease severity with Zellweger syndrome (ZS) being the most severe. In contrast to patients with the ZS phenotype, mild patients can be characterized by very mildly abnormal peroxisomal parameters in cultured skin fi broblasts, including a mosaic catalase immunofl uorescence pattern. Such a mosaic pattern is described for specifi c missense mutations in various PEX genes. Possibly, these missense mutations cause an unstable and/or incorrect folded native state of the protein. We hypothesize that the functional activity of the mutant PEX1 can be enhanced by promoting protein folding with chemical chaperones (e.g. glycerol or arginine) and thereby stimulating peroxisome biogenesis. METHODS Fibroblasts from four patients with a defect in PEX1 and two controls were cultured for up to three weeks in DMEM medium with diff erent concentrations of arginine or glycerol. To determine the eff ect of diff erent chemicals on peroxisome biogenesis we studied the following parameters: (1) the levels of PEX1 protein, (2) the peroxisomal protein import capacity, (3) the levels of intra peroxisomal processed protein, and (4) the capacity to β-oxidize very long chain fatty acids. CONCLUSION The addition of arginine or glycerol to the medium improved both the peroxisomal biogenesis and the peroxisomal metabolic state of fi broblasts with a missense mutation in PEX1. We hypothesize that a signifi cant number of ZSS patients may benefi t from arginine treatment.