title: N-acetyl cysteine treatment rescues cognitive deficits induced by mitochondrial dysfunction in G72/G30 transgenic mice.
abstract: Genetic studies have implicated the evolutionary novel, anthropoid primate-specific gene locus G72/G30 in psychiatric diseases. This gene encodes the protein LG72 that has been discussed to function as a putative activator of the peroxisomal enzyme D-amino-acid-oxidase (DAO) and as a mitochondrial protein. We recently generated 'humanized' bacterial artificial chromosome transgenic mice (G72Tg) expressing G72 transcripts in cells throughout the brain. These mice exhibit several behavioral phenotypes related to psychiatric diseases. Here we show that G72Tg mice have a reduced activity of mitochondrial complex I, with a concomitantly increased production of reactive oxygen species. Affected neurons display deficits in short-term plasticity and an impaired capability to sustain synaptic activity. These deficits lead to an impairment in spatial memory, which can be rescued by pharmacological treatment with the glutathione precursor N-acetyl cysteine. Our results implicate LG72-induced mitochondrial and synaptic defects as a possible pathomechanism of psychiatric disorders.
authors.affiliation: Institute of Molecular Psychiatry, University of Bonn, Bonn, Germany.
authors.forename: David-Marian
authors.initials: DM
authors.lastname: Otte
authors.forename: Britta
authors.initials: B
authors.lastname: Sommersberg
authors.forename: Alexei
authors.initials: A
authors.lastname: Kudin
authors.forename: Catalina
authors.initials: C
authors.lastname: Guerrero
authors.forename: Onder
authors.initials: O
authors.lastname: Albayram
authors.forename: Michaela D
authors.initials: MD
authors.lastname: Filiou
authors.forename: Pamela
authors.initials: P
authors.lastname: Frisch
authors.forename: Oznur
authors.initials: O
authors.lastname: Yilmaz
authors.forename: Eva
authors.initials: E
authors.lastname: Drews
authors.forename: Christoph W
authors.initials: CW
authors.lastname: Turck
authors.forename: Andras
authors.initials: A
authors.lastname: Bilkei-Gorzó
authors.forename: Wolfram S
authors.initials: WS
authors.lastname: Kunz
authors.forename: Heinz
authors.initials: H
authors.lastname: Beck
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
mesh_terms: D000111:Acetylcysteine / Q000627:therapeutic use*; D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D003072:Cognition Disorders / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D042967:Electron Transport Complex I / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D028361:Mitochondrial Diseases / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D002352:Carrier Proteins; C475071:DAOA protein, human; D047908:Intracellular Signaling Peptides and Proteins; D017382:Reactive Oxygen Species; D042967:Electron Transport Complex I; D000111:Acetylcysteine