title: Loss of DJ-1 impairs antioxidant response by altered glutamine and serine metabolism.
abstract: 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.
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4367 Belvaux, Luxembourg.
authors.forename: J
authors.initials: J
authors.lastname: Meiser
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4367 Belvaux, Luxembourg.
authors.forename: S
authors.initials: S
authors.lastname: Delcambre
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4367 Belvaux, Luxembourg.
authors.forename: A
authors.initials: A
authors.lastname: Wegner
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4367 Belvaux, Luxembourg.
authors.forename: C
authors.initials: C
authors.lastname: Jäger
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4367 Belvaux, Luxembourg.
authors.forename: J
authors.initials: J
authors.lastname: Ghelfi
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4367 Belvaux, Luxembourg.
authors.forename: A Fouquier
authors.initials: AF
authors.lastname: d'Herouel
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4367 Belvaux, Luxembourg.
authors.forename: X
authors.initials: X
authors.lastname: Dong
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4367 Belvaux, Luxembourg.
authors.forename: D
authors.initials: D
authors.lastname: Weindl
authors.affiliation: Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Developmental Genetics, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Stautner
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4367 Belvaux, Luxembourg.
authors.forename: Y
authors.initials: Y
authors.lastname: Nonnenmacher
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4367 Belvaux, Luxembourg; NorLux Neuro-Oncology Laboratory, Luxembourg Institute of Health, 84, Val Fleuri, L-1526, Luxembourg.
authors.forename: A
authors.initials: A
authors.lastname: Michelucci
authors.affiliation: Mass Spectrometry Core Facility, Max-Delbrueck Center for Molecular Medicine, Robert-Roessle Strasse 10, 13125 Berlin, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Popp
authors.affiliation: Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Developmental Genetics, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Giesert
authors.affiliation: Doerenkamp-Zbinden Chair for In Vitro Toxicology and Biomedicine, University of Konstanz, Konstanz D-78457, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schildknecht
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4367 Belvaux, Luxembourg.
authors.forename: L
authors.initials: L
authors.lastname: Krämer
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4367 Belvaux, Luxembourg; Saarland University Medical Center, Department of Internal Medicine II, Homburg/Saar, Germany.
authors.forename: J G
authors.initials: JG
authors.lastname: Schneider
authors.affiliation: Neurology, St. Josef Hospital, Ruhr-University, Gudrunstr. 56, 44780 Bochum, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Woitalla
authors.affiliation: Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Developmental Genetics, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany; Deutsches Zentrum für Neurodegenerative Erkrankungen e. V. (DZNE) Standort München, Feodor-Lynen-Strasse 17, 81377 München, Germany; Munich Cluster for Systems Neurology (SyNergy), Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität München, Schillerstrasse 44, 80336 München, Germany; Technische Universität München-Weihenstephan, Lehrstuhl für Entwicklungsgenetik, c/o Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Wurst
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4367 Belvaux, Luxembourg; National Center for Microscopy and Imaging Research, University of California San Diego, La Jolla, CA, United States.
authors.forename: A
authors.initials: A
authors.lastname: Skupin
authors.affiliation: Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Developmental Genetics, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
authors.forename: D M Vogt
authors.initials: DM
authors.lastname: Weisenhorn
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4367 Belvaux, Luxembourg.
authors.forename: R
authors.initials: R
authors.lastname: Krüger
authors.affiliation: Doerenkamp-Zbinden Chair for In Vitro Toxicology and Biomedicine, University of Konstanz, Konstanz D-78457, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Leist
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4367 Belvaux, Luxembourg. Electronic address: karsten.hiller@uni.lu.
authors.forename: K
authors.initials: K
authors.lastname: Hiller
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D002478:Cells, Cultured; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D055442:Metabolome; D051379:Mice; D017628:Microglia / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D018384:Oxidative Stress; D000071617:Protein Deglycase DJ-1 / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D005973:Glutamine; D012694:Serine; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1
keywords: Folate mediated one-carbon metabolism; GC/MS; Glutamine; Glutathione; Mitochondrial metabolism; Oxidative stress; Parkinson's disease; ROS; Serine; Stable isotope-assisted metabolomics