title: Oxidative damage compromises energy metabolism in the axonal degeneration mouse model of X-adrenoleukodystrophy.
abstract: OBJECTIVE
  Chronic metabolic impairment and oxidative stress are associated with the pathogenesis of axonal dysfunction in a growing number of neurodegenerative conditions. To investigate the intertwining of both noxious factors, we have chosen the mouse model of adrenoleukodystrophy (X-ALD), which exhibits axonal degeneration in spinal cords and motor disability. The disease is caused by loss of function of the ABCD1 transporter, involved in the import and degradation of very long-chain fatty acids (VLCFA) in peroxisomes. Oxidative stress due to VLCFA excess appears early in the neurodegenerative cascade.
  
  
  RESULTS
  In this study, we demonstrate by redox proteomics that oxidative damage to proteins specifically affects five key enzymes of glycolysis and TCA (Tricarboxylic acid) cycle in spinal cords of Abcd1(-) mice and pyruvate kinase in human X-ALD fibroblasts. We also show that NADH and ATP levels are significantly diminished in these samples, together with decrease of pyruvate kinase activities and GSH levels, and increase of NADPH.
  
  
  METHODS
  Treating Abcd1(-) mice with the antioxidants N-acetylcysteine and α-lipoic acid (LA) prevents protein oxidation; preserves NADH, NADPH, ATP, and GSH levels; and normalizes pyruvate kinase activity, which implies that oxidative stress provoked by VLCFA results in bioenergetic dysfunction, at a presymptomatic stage.
  
  
  CONCLUSIONS
  Our results provide mechanistic insight into the beneficial effects of antioxidants and enhance the rationale for translation into clinical trials for X-adrenoleukodystrophy.
authors: Neurometabolic Diseases Laboratory, Institut d'Investigació Biomèdica de Bellvitge, Hospitalet de Llobregat, Gran Via 199, Barcelona, Spain .
authors: Jorge
authors: J
authors: Galino
authors: Montserrat
authors: M
authors: Ruiz
authors: Stéphane
authors: S
authors: Fourcade
authors: Agatha
authors: A
authors: Schlüter
authors: Jone
authors: J
authors: López-Erauskin
authors: Cristina
authors: C
authors: Guilera
authors: Mariona
authors: M
authors: Jove
authors: Alba
authors: A
authors: Naudi
authors: Elena
authors: E
authors: García-Arumí
authors: Antoni L
authors: AL
authors: Andreu
authors: Anatoly A
authors: AA
authors: Starkov
authors: Reinald
authors: R
authors: Pamplona
authors: Isidre
authors: I
authors: Ferrer
authors: Manuel
authors: M
authors: Portero-Otin
authors: Aurora
authors: A
authors: Pujol
mesh_terms: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000326:Adrenoleukodystrophy / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015180:Electrophoresis, Gel, Two-Dimensional; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009243:NAD / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*; D040901:Proteomics; D011770:Pyruvate Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; C552836:Abcd1 protein, mouse; D009243:NAD; D000255:Adenosine Triphosphate; D011770:Pyruvate Kinase; D005978:Glutathione