Human IPSC 3D brain model as a tool to study chemical-induced dopaminergic neuronal toxicity

Lade...
Vorschaubild
Dateien
Pamies_2-1kznpu14p9xq5.pdf
Pamies_2-1kznpu14p9xq5.pdfGröße: 10.54 MBDownloads: 108
Datum
2022
Autor:innen
Pamies, David
Wiersma, Daphne
Katt, Moriah E.
Zhao, Liang
Burtscher, Johannes
Harris, Georgina
Smirnova, Lena
Searson, Peter C.
Hogberg, Helena T.
Herausgeber:innen
Kontakt
ISSN der Zeitschrift
Electronic ISSN
ISBN
Bibliografische Daten
Verlag
Schriftenreihe
Auflagebezeichnung
ArXiv-ID
Internationale Patentnummer
Link zur Lizenz
Angaben zur Forschungsförderung
Projekt
Open Access-Veröffentlichung
Open Access Hybrid
Sammlungen
Core Facility der Universität Konstanz
Gesperrt bis
Titel in einer weiteren Sprache
Publikationstyp
Zeitschriftenartikel
Publikationsstatus
Published
Erschienen in
Neurobiology of disease. Elsevier. 2022, 169, 105719. ISSN 0969-9961. eISSN 1095-953X. Available under: doi: 10.1016/j.nbd.2022.105719
Zusammenfassung

Oxidative stress is caused by an imbalance between the generation and detoxification of reactive oxygen and nitrogen species (ROS/RNS). This imbalance plays an important role in brain aging and age-related neurodegenerative diseases. In the context of Parkinson's disease (PD), the sensitivity of dopaminergic neurons in the substantia nigra pars compacta to oxidative stress is considered a key factor of PD pathogenesis. Here we study the effect of different oxidative stress-inducing compounds (6-OHDA, MPTP or MPP+) on the population of dopaminergic neurons in an iPSC-derived human brain 3D model (aka BrainSpheres). Treatment with 6-OHDA, MPTP or MPP+ at 4 weeks of differentiation disrupted the dopaminergic neuronal phenotype in BrainSpheres at (50, 5000, 1000 μM respectively). 6-OHDA increased ROS production and decreased mitochondrial function most efficiently. It further induced the greatest changes in gene expression and metabolites related to oxidative stress and mitochondrial dysfunction. Co-culturing BrainSpheres with an endothelial barrier using a transwell system allowed the assessment of differential penetration capacities of the tested compounds and the damage they caused in the dopaminergic neurons within the BrainSpheres In conclusion, treatment with compounds known to induce PD-like phenotypes in vivo caused molecular deficits and loss of dopaminergic neurons in the BrainSphere model. This approach therefore recapitulates common animal models of neurodegenerative processes in PD at similarly high doses. The relevance as tool for drug discovery is discussed.

Zusammenfassung in einer weiteren Sprache
Fachgebiet (DDC)
570 Biowissenschaften, Biologie
Schlagwörter
Toxicant-induced Parkinson's disease, Microphysiological system, Organoid 3d culture, Stem cells, iPSC, MPP+, MPTP, 6OHDA
Konferenz
Rezension
undefined / . - undefined, undefined
Forschungsvorhaben
Organisationseinheiten
Zeitschriftenheft
Datensätze
Zitieren
ISO 690PAMIES, David, Daphne WIERSMA, Moriah E. KATT, Liang ZHAO, Johannes BURTSCHER, Georgina HARRIS, Lena SMIRNOVA, Peter C. SEARSON, Thomas HARTUNG, Helena T. HOGBERG, 2022. Human IPSC 3D brain model as a tool to study chemical-induced dopaminergic neuronal toxicity. In: Neurobiology of disease. Elsevier. 2022, 169, 105719. ISSN 0969-9961. eISSN 1095-953X. Available under: doi: 10.1016/j.nbd.2022.105719
BibTex
@article{Pamies2022-07Human-57797,
  year={2022},
  doi={10.1016/j.nbd.2022.105719},
  title={Human IPSC 3D brain model as a tool to study chemical-induced dopaminergic neuronal toxicity},
  volume={169},
  issn={0969-9961},
  journal={Neurobiology of disease},
  author={Pamies, David and Wiersma, Daphne and Katt, Moriah E. and Zhao, Liang and Burtscher, Johannes and Harris, Georgina and Smirnova, Lena and Searson, Peter C. and Hartung, Thomas and Hogberg, Helena T.},
  note={Article Number: 105719}
}
RDF
<rdf:RDF
    xmlns:dcterms="http://purl.org/dc/terms/"
    xmlns:dc="http://purl.org/dc/elements/1.1/"
    xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#"
    xmlns:bibo="http://purl.org/ontology/bibo/"
    xmlns:dspace="http://digital-repositories.org/ontologies/dspace/0.1.0#"
    xmlns:foaf="http://xmlns.com/foaf/0.1/"
    xmlns:void="http://rdfs.org/ns/void#"
    xmlns:xsd="http://www.w3.org/2001/XMLSchema#" > 
  <rdf:Description rdf:about="https://kops.uni-konstanz.de/server/rdf/resource/123456789/57797">
    <dcterms:hasPart rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/57797/1/Pamies_2-1kznpu14p9xq5.pdf"/>
    <dc:contributor>Wiersma, Daphne</dc:contributor>
    <bibo:uri rdf:resource="https://kops.uni-konstanz.de/handle/123456789/57797"/>
    <dc:contributor>Hogberg, Helena T.</dc:contributor>
    <dcterms:rights rdf:resource="http://creativecommons.org/licenses/by-nc-nd/4.0/"/>
    <dc:contributor>Harris, Georgina</dc:contributor>
    <dc:creator>Hogberg, Helena T.</dc:creator>
    <dcterms:issued>2022-07</dcterms:issued>
    <dc:creator>Katt, Moriah E.</dc:creator>
    <dc:contributor>Zhao, Liang</dc:contributor>
    <dcterms:abstract xml:lang="eng">Oxidative stress is caused by an imbalance between the generation and detoxification of reactive oxygen and nitrogen species (ROS/RNS). This imbalance plays an important role in brain aging and age-related neurodegenerative diseases. In the context of Parkinson's disease (PD), the sensitivity of dopaminergic neurons in the substantia nigra pars compacta to oxidative stress is considered a key factor of PD pathogenesis. Here we study the effect of different oxidative stress-inducing compounds (6-OHDA, MPTP or MPP+) on the population of dopaminergic neurons in an iPSC-derived human brain 3D model (aka BrainSpheres). Treatment with 6-OHDA, MPTP or MPP+ at 4 weeks of differentiation disrupted the dopaminergic neuronal phenotype in BrainSpheres at (50, 5000, 1000 μM respectively). 6-OHDA increased ROS production and decreased mitochondrial function most efficiently. It further induced the greatest changes in gene expression and metabolites related to oxidative stress and mitochondrial dysfunction. Co-culturing BrainSpheres with an endothelial barrier using a transwell system allowed the assessment of differential penetration capacities of the tested compounds and the damage they caused in the dopaminergic neurons within the BrainSpheres In conclusion, treatment with compounds known to induce PD-like phenotypes in vivo caused molecular deficits and loss of dopaminergic neurons in the BrainSphere model. This approach therefore recapitulates common animal models of neurodegenerative processes in PD at similarly high doses. The relevance as tool for drug discovery is discussed.</dcterms:abstract>
    <dc:creator>Pamies, David</dc:creator>
    <dc:contributor>Hartung, Thomas</dc:contributor>
    <dc:creator>Hartung, Thomas</dc:creator>
    <dc:contributor>Katt, Moriah E.</dc:contributor>
    <dspace:isPartOfCollection rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/28"/>
    <dc:creator>Zhao, Liang</dc:creator>
    <dc:rights>Attribution-NonCommercial-NoDerivatives 4.0 International</dc:rights>
    <dc:language>eng</dc:language>
    <foaf:homepage rdf:resource="http://localhost:8080/"/>
    <dc:contributor>Smirnova, Lena</dc:contributor>
    <dc:creator>Searson, Peter C.</dc:creator>
    <dc:creator>Wiersma, Daphne</dc:creator>
    <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2022-06-17T07:30:41Z</dc:date>
    <dc:creator>Smirnova, Lena</dc:creator>
    <dc:contributor>Pamies, David</dc:contributor>
    <dc:contributor>Burtscher, Johannes</dc:contributor>
    <dspace:hasBitstream rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/57797/1/Pamies_2-1kznpu14p9xq5.pdf"/>
    <dcterms:isPartOf rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/28"/>
    <void:sparqlEndpoint rdf:resource="http://localhost/fuseki/dspace/sparql"/>
    <dc:creator>Burtscher, Johannes</dc:creator>
    <dc:creator>Harris, Georgina</dc:creator>
    <dc:contributor>Searson, Peter C.</dc:contributor>
    <dcterms:available rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2022-06-17T07:30:41Z</dcterms:available>
    <dcterms:title>Human IPSC 3D brain model as a tool to study chemical-induced dopaminergic neuronal toxicity</dcterms:title>
  </rdf:Description>
</rdf:RDF>
Interner Vermerk
xmlui.Submission.submit.DescribeStep.inputForms.label.kops_note_fromSubmitter
Kontakt
URL der Originalveröffentl.
Prüfdatum der URL
Prüfungsdatum der Dissertation
Finanzierungsart
Kommentar zur Publikation
Allianzlizenz
Corresponding Authors der Uni Konstanz vorhanden
Internationale Co-Autor:innen
Universitätsbibliographie
Ja
Begutachtet
Ja
Diese Publikation teilen