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Meiser, J.* ; Delcambre, S.* ; Wegner, A.* ; Jager, C.* ; Ghelfi, J.* ; D'Herouel, A.F.* ; Dong, X.* ; Weindl, D.* ; Stautner, C. ; Nonnenmacher, Y.* ; Michelucci, A.* ; Popp, O.* ; Giesert, F.H.H. ; Schildknecht, S.* ; Krämer, L.* ; Schneider, J.G.* ; Woitalla, D.* ; Wurst, W. ; Skupin, A.* ; Weisenhorn, D.M. ; Kruger, R.* ; Leist, M.* ; Hiller, K.*

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

Neurobiol. Dis. 89, 112-125 (2016)
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Open Access Green
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Folate Mediated One-carbon Metabolism ; Gc/ms ; Glutamine ; Glutathione ; Mitochondrial Metabolism ; Oxidative Stress ; Parkinson's Disease ; Ros ; Serine ; Stable Isotope-assisted Metabolomics; Pyruvate-kinase M2; Disease-associated Protein; Early-onset Parkinsonism; Tumor-suppressor Pten; Oxidative Stress; Cell-survival; Glutathione Synthesis; Itaconic Acid; Neurons; Regulator
ISSN (print) / ISBN 0969-9961
e-ISSN 1095-953X
Quellenangaben Band: 89, Heft: , Seiten: 112-125 Artikelnummer: , Supplement: ,
Verlag Elsevier
Verlagsort San Diego
Begutachtungsstatus Peer reviewed