[en] The oncogene DJ-1 has been originally identified as a suppressor of PTEN. Further on, loss-of-function mutations have been described as a causative factor in Parkinson's disease (PD). DJ-1 has an important function in cellular antioxidant responses, but its role in central metabolism of neurons is still elusive. We applied stable isotope assisted metabolic profiling to investigate the effect of a functional loss of DJ-1 and show that DJ-1 deficient neuronal cells exhibit decreased glutamine influx and reduced serine biosynthesis. By providing precursors for GSH synthesis, these two metabolic pathways are important contributors to cellular antioxidant response. Down-regulation of these pathways, as a result of loss of DJ-1 leads to an impaired antioxidant response. Furthermore, DJ-1 deficient mouse microglia showed a weak but constitutive pro-inflammatory activation. The combined effects of altered central metabolism and constitutive activation of glia cells raise the susceptibility of dopaminergic neurons towards degeneration in patients harboring mutated DJ-1. Our work reveals metabolic alterations leading to increased cellular instability and identifies potential new intervention points that can further be studied in the light of novel translational medicine approaches.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Meiser, Johannes ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Delcambre, Sylvie ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Wegner, André ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Jäger, Christian ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Ghelfi, Jenny ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Dong, Xiangyi ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Weindl, Daniel ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Stautner, Constantin; Helmholtz Zentrum München - HZM > Institute of Developmental Genetics
Nonnenmacher, Yannic ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Michelucci, Alessandro ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Popp, Oliver; Max-Delbrueck Center for Molecular Medicine - MDC > Mass Spectrometry Core Facility
Giesert, Florian; Helmholtz Zentrum München - HZM > Institute of Developmental Genetics
Schildknecht, Stefan; University of Konstanz - UK > Doerenkamp-Zbinden Chair for In Vitro Toxicology and Biomedicine
Kraemer, Lisa ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Schneider, Jochen G.; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) ; Saarland University Medical Center - UKS > Department of Internal Medicine II
Woitalla, Dirk; Ruhr-University - RUB > St. Josef Hospital > Neurology
Wurst, Wolfgang; Helmholtz Zentrum München - HZM > Institute of Developmental Genetics ; Deutsches Zentrum fur Neurodegenerative Erkrankungen e. V. - DZNE ; Ludwig-Maximilians-Universität München - LMU > Adolf-Butenandt-Institut > Munich Cluster for Systems Neurology (SyNergy)
Skupin, Alexander ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) ; University of California San Diego - UCSD > National Center for Microscopy and Imaging Research
Vogt Weisenhorn, Daniela M.; Helmholtz Zentrum München - HZM > Institute of Developmental Genetics
Krüger, Rejko ; University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Leist, Marcel; University of Konstanz - UK > Doerenkamp-Zbinden Chair for In Vitro Toxicology and Biomedicine
Hiller, Karsten ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)