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Loss of DJ-1 impairs antioxidant response by altered glutamine and serine metabolism

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Item Type:Article
Title:Loss of DJ-1 impairs antioxidant response by altered glutamine and serine metabolism
Creators Name:Meiser, J. and Delcambre, S. and Wegner, A. and Jaeger, C. and Ghelfi, J. and D'Herouel, A.F. and Dong, X. and Weindl, D. and Stautner, C. and Nonnenmacher, Y. and Michelucci, A. and Popp, O. and Giesert, F. and Schildknecht, S. and Kraemer, L. and Schneider, J.G. and Woitalla, D. and Wurst, W. and Skupin, A. and Weisenhorn, D.M.V. and Krueger, R. and Leist, M. and Hiller, K.
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.
Keywords:Parkinson's Disease, Mitochondrial Metabolism, Glutamine, Serine, Folate Mediated One-Carbon Metabolism, Oxidative Stress, ROS, Glutathione, Stable Isotope-Assisted Metabolomics, GC/MS, Animals, Mice
Source:Neurobiology of Disease
Publisher:Elsevier / Academic Press
Page Range:112-125
Date:May 2016
Additional Information:Copyright © 2016 The Authors
Official Publication:https://doi.org/10.1016/j.nbd.2016.01.019
PubMed:View item in PubMed

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