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  Protein signatures of oxidative stress response in a patient specific cell line model for autism

Chiocchetti, A. G., Haslinger, D., Boesch, M., Karl, T., Wiemann, S., Freitag, C. M., et al. (2014). Protein signatures of oxidative stress response in a patient specific cell line model for autism. MOLECULAR AUTISM, 5: 10. doi:10.1186/2040-2392-5-10.

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Chiocchetti, Andreas G.1, Author
Haslinger, Denise1, Author
Boesch, Maximilian1, Author
Karl, Thomas1, Author
Wiemann, Stefan1, Author
Freitag, Christine M.1, Author
Poustka, Fritz1, Author
Scheibe, Burghardt1, Author
Bauer, Johann W.1, Author
Hintner, Helmut1, Author
Breitenbach, Michael1, Author
Kellermann, Josef2, Author              
Lottspeich, Friedrich2, Author              
Klauck, Sabine M.1, Author
Breitenbach-Koller, Lore1, Author
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1external, ou_persistent22              
2Lottspeich, Friedrich / Protein Analysis, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565158              

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Free keywords: COPY-NUMBER VARIATION; SPECTRUM DISORDERS; SACCHAROMYCES-CEREVISIAE; MITOCHONDRIAL DYSFUNCTION; BIOLOGICAL NETWORKS; EXPRESSION ANALYSES; CYTOSCAPE PLUGIN; GENE-FUNCTION; MUTATION; DAMAGEAutism spectrum disorder; RPL10; Translation; Protein expression; Redox-sensitive protein signature; Oxidative stress response; Energy metabolism;
 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.

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Language(s): eng - English
 Dates: 2014
 Publication Status: Published online
 Pages: 15
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: ISI: 000334713800001
DOI: 10.1186/2040-2392-5-10
 Degree: -

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Title: MOLECULAR AUTISM
Source Genre: Journal
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Publ. Info: 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND : BIOMED CENTRAL LTD
Pages: - Volume / Issue: 5 Sequence Number: 10 Start / End Page: - Identifier: ISSN: 2040-2392