title: Evidence of oxidative stress in very long chain fatty acid--treated oligodendrocytes and potentialization of ROS production using RNA interference-directed knockdown of ABCD1 and ACOX1 peroxisomal proteins.
abstract: X-linked adrenoleukodystrophy (X-ALD) and pseudo neonatal adrenoleukodystrophy (P-NALD) are neurodegenerative demyelinating diseases resulting from the functional loss of the peroxisomal ATP-binding cassette transporter D (ABCD1) and from single peroxisomal enzyme deficiency (Acyl-CoA oxidase1: ACOX1), respectively. As these proteins are involved in the catabolism of very long chain fatty acids (VLCFA: C24:0, C26:0), X-ALD and P-NALD patients are characterized by the accumulation of VLCFA in plasma and tissues. Since peroxisomes are involved in the metabolism of reactive oxygen species (ROS) and nitrogen species (RNS), we examined the impact of VLCFA on the oxidative status of 158N murine oligodendrocytes expressing or not Abcd1 or Acox1. VLCFA triggers an oxidative stress characterized by an overproduction of ROS and RNS associated with lipid peroxidation, protein carbonylation, increased superoxide dismutase (SOD) activity, decreased catalase activity and glutathione level. SiRNA knockdown of Abcd1 or Acox1 increased ROS and RNS production even in the absence of VLCFA, and especially potentialized VLCFA-induced ROS overproduction. Moreover, mainly in cells with reduced Acox1 level, the levels of VLCFA and neutral lipids were strongly enhanced both in untreated and VLCFA - treated cells. Our data obtained on 158N murine oligodendrocytes highlight that VLCFA induce an oxidative stress, and demonstrate that Abcd1 or Acox1 knockdown contributes to disrupt RedOx equilibrium supporting a link between oxidative stress and the deficiency of Abcd1 or Acox1 peroxisomal proteins.
authors.affiliation: Equipe Biochimie du Peroxysome, Inflammation et Métabolisme Lipidique, Université de Bourgogne, EA7270, Dijon, France.
authors.forename: M
authors.initials: M
authors.lastname: Baarine
authors.forename: P
authors.initials: P
authors.lastname: Andréoletti
authors.forename: A
authors.initials: A
authors.lastname: Athias
authors.forename: T
authors.initials: T
authors.lastname: Nury
authors.forename: A
authors.initials: A
authors.lastname: Zarrouk
authors.forename: K
authors.initials: K
authors.lastname: Ragot
authors.forename: A
authors.initials: A
authors.lastname: Vejux
authors.forename: J-M
authors.initials: JM
authors.lastname: Riedinger
authors.forename: Z
authors.initials: Z
authors.lastname: Kattan
authors.forename: G
authors.initials: G
authors.lastname: Bessede
authors.forename: D
authors.initials: D
authors.lastname: Trompier
authors.forename: S
authors.initials: S
authors.lastname: Savary
authors.forename: M
authors.initials: M
authors.lastname: Cherkaoui-Malki
authors.forename: G
authors.initials: G
authors.lastname: Lizard
mesh_terms: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D042962:Acyl-CoA Oxidase / Q000235:genetics / Q000378:metabolism*; D000326:Adrenoleukodystrophy / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D005227:Fatty Acids / Q000378:metabolism* / Q000494:pharmacology; D005434:Flow Cytometry; D008401:Gas Chromatography-Mass Spectrometry; D055785:Gene Knockdown Techniques; D051379:Mice; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D020675:Peroxisomes / Q000378:metabolism; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; C552836:Abcd1 protein, mouse; D005227:Fatty Acids; D017382:Reactive Oxygen Species; D042962:Acyl-CoA Oxidase