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Caenorhabditis elegans as a model system to study post-translational modifications of human transthyretin

  • The visceral protein transthyretin (TTR) is frequently affected by oxidative post-translational protein modifications (PTPMs) in various diseases. Thus, better insight into structure-function relationships due to oxidative PTPMs of TTR should contribute to the understanding of pathophysiologic mechanisms. While the in vivo analysis of TTR in mammalian models is complex, time- and resource-consuming, transgenic Caenorhabditis elegans expressing hTTR provide an optimal model for the in vivo identification and characterization of drug-mediated oxidative PTPMs of hTTR by means of matrix assisted laser desorption/ionization – time of flight – mass spectrometry (MALDI-TOF-MS). Herein, we demonstrated that hTTR is expressed in all developmental stages of Caenorhabditis elegans, enabling the analysis of hTTR metabolism during the whole life-cycle. The suitability of the applied model was verified by exposing worms to D-penicillamine and menadione. Both drugs induced substantial changes in the oxidative PTPM pattern of hTTR. Additionally, forThe visceral protein transthyretin (TTR) is frequently affected by oxidative post-translational protein modifications (PTPMs) in various diseases. Thus, better insight into structure-function relationships due to oxidative PTPMs of TTR should contribute to the understanding of pathophysiologic mechanisms. While the in vivo analysis of TTR in mammalian models is complex, time- and resource-consuming, transgenic Caenorhabditis elegans expressing hTTR provide an optimal model for the in vivo identification and characterization of drug-mediated oxidative PTPMs of hTTR by means of matrix assisted laser desorption/ionization – time of flight – mass spectrometry (MALDI-TOF-MS). Herein, we demonstrated that hTTR is expressed in all developmental stages of Caenorhabditis elegans, enabling the analysis of hTTR metabolism during the whole life-cycle. The suitability of the applied model was verified by exposing worms to D-penicillamine and menadione. Both drugs induced substantial changes in the oxidative PTPM pattern of hTTR. Additionally, for the first time a covalent binding of both drugs with hTTR was identified and verified by molecular modelling.show moreshow less

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Metadaten
Author:Andrea HenzeORCiDGND, Thomas Homann, Isabelle Rohn, Michael Aschner, Christopher D. Link, Burkhard KleuserORCiDGND, Florian J. SchweigertORCiDGND, Tanja Schwerdtle, Julia Bornhorst
DOI:https://doi.org/10.1038/srep37346
ISSN:2045-2322
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=27869126
Parent Title (English):Scientific reports
Publisher:Nature Publishing Group
Place of publication:London
Document Type:Article
Language:English
Date of first Publication:2016/11/21
Year of Completion:2016
Publishing Institution:Universität Potsdam
Release Date:2017/02/22
Tag:binding; c. elegans; cells; disease; force-field; life-span; menadione; n-acetyl-cysteine; protein; s-glutathionylation
Volume:6
Pagenumber:12
Funder:Universität Potsdam, Publikationsfonds
Grant Number:PA 2016_41
Organizational units:Mathematisch-Naturwissenschaftliche Fakultät / Institut für Ernährungswissenschaft
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 50 Naturwissenschaften / 500 Naturwissenschaften und Mathematik
5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften
Peer Review:Referiert
Grantor:Publikationsfonds der Universität Potsdam
Publication Way:Open Access
Licence (German):License LogoCreative Commons - Namensnennung, 4.0 International
Notes extern:Zweitveröffentlichung in der Schriftenreihe Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe ; 312