title: Protein signatures of oxidative stress response in a patient specific cell line model for autism.
abstract: BACKGROUND
  Known genetic variants can account for 10% to 20% of all cases with autism spectrum disorders (ASD). Overlapping cellular pathomechanisms common to neurons of the central nervous system (CNS) and in tissues of peripheral organs, such as immune dysregulation, oxidative stress and dysfunctions in mitochondrial and protein synthesis metabolism, were suggested to support the wide spectrum of ASD on unifying disease phenotype. Here, we studied in patient-derived lymphoblastoid cell lines (LCLs) how an ASD-specific mutation in ribosomal protein RPL10 (RPL10[H213Q]) generates a distinct protein signature. We compared the RPL10[H213Q] expression pattern to expression patterns derived from unrelated ASD patients without RPL10[H213Q] mutation. In addition, a yeast rpl10 deficiency model served in a proof-of-principle study to test for alterations in protein patterns in response to oxidative stress.
  
  
  METHODS
  Protein extracts of LCLs from patients, relatives and controls, as well as diploid yeast cells hemizygous for rpl10, were subjected to two-dimensional gel electrophoresis and differentially regulated spots were identified by mass spectrometry. Subsequently, Gene Ontology database (GO)-term enrichment and network analysis was performed to map the identified proteins into cellular pathways.
  
  
  RESULTS
  The protein signature generated by RPL10[H213Q] is a functionally related subset of the ASD-specific protein signature, sharing redox-sensitive elements in energy-, protein- and redox-metabolism. In yeast, rpl10 deficiency generates a specific protein signature, harboring components of pathways identified in both the RPL10[H213Q] subjects' and the ASD patients' set. Importantly, the rpl10 deficiency signature is a subset of the signature resulting from response of wild-type yeast to oxidative stress.
  
  
  CONCLUSIONS
  Redox-sensitive protein signatures mapping into cellular pathways with pathophysiology in ASD have been identified in both LCLs carrying the ASD-specific mutation RPL10[H213Q] and LCLs from ASD patients without this mutation. At pathway levels, this redox-sensitive protein signature has also been identified in a yeast rpl10 deficiency and an oxidative stress model. These observations point to a common molecular pathomechanism in ASD, characterized in our study by dysregulation of redox balance. Importantly, this can be triggered by the known ASD-RPL10[H213Q] mutation or by yet unknown mutations of the ASD cohort that act upstream of RPL10 in differential expression of redox-sensitive proteins.
authors: Division of Molecular Genome Analysis, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.|Department of Cell Biology, University of Salzburg, Hellbrunnerstr. 34, 5020 Salzburg, Austria.|Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, J.W. Goethe University, Deutschordenstr. 50, 60528 Frankfurt am Main, Germany.
authors: Andreas G
authors: AG
authors: Chiocchetti
authors: Department of Cell Biology, University of Salzburg, Hellbrunnerstr. 34, 5020 Salzburg, Austria.|Division of Molecular Genome Analysis, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.|Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, J.W. Goethe University, Deutschordenstr. 50, 60528 Frankfurt am Main, Germany.
authors: Denise
authors: D
authors: Haslinger
authors: Department of Cell Biology, University of Salzburg, Hellbrunnerstr. 34, 5020 Salzburg, Austria.
authors: Maximilian
authors: M
authors: Boesch
authors: Department of Cell Biology, University of Salzburg, Hellbrunnerstr. 34, 5020 Salzburg, Austria.
authors: Thomas
authors: T
authors: Karl
authors: Division of Molecular Genome Analysis, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
authors: Stefan
authors: S
authors: Wiemann
authors: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, J.W. Goethe University, Deutschordenstr. 50, 60528 Frankfurt am Main, Germany.
authors: Christine M
authors: CM
authors: Freitag
authors: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, J.W. Goethe University, Deutschordenstr. 50, 60528 Frankfurt am Main, Germany.
authors: Fritz
authors: F
authors: Poustka
authors: Department of Cell Biology, University of Salzburg, Hellbrunnerstr. 34, 5020 Salzburg, Austria.
authors: Burghardt
authors: B
authors: Scheibe
authors: Department of Dermatology, General Hospital Salzburg/PMU, Müllner-Hauptstr. 48, 5020 Salzburg, Austria.
authors: Johann W
authors: JW
authors: Bauer
authors: Department of Dermatology, General Hospital Salzburg/PMU, Müllner-Hauptstr. 48, 5020 Salzburg, Austria.
authors: Helmut
authors: H
authors: Hintner
authors: Department of Cell Biology, University of Salzburg, Hellbrunnerstr. 34, 5020 Salzburg, Austria.
authors: Michael
authors: M
authors: Breitenbach
authors: Max-Planck-Institute of Biochemistry, Protein Analysis Group, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors: Josef
authors: J
authors: Kellermann
authors: Max-Planck-Institute of Biochemistry, Protein Analysis Group, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors: Friedrich
authors: F
authors: Lottspeich
authors: Division of Molecular Genome Analysis, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
authors: Sabine M
authors: SM
authors: Klauck
authors: Department of Cell Biology, University of Salzburg, Hellbrunnerstr. 34, 5020 Salzburg, Austria.
authors: Lore
authors: L
authors: Breitenbach-Koller