NUB1 modulation of GSK3β reduces tau aggregation

Lade...
Vorschaubild
Dateien
Richet_219910.pdf
Richet_219910.pdfGröße: 2.07 MBDownloads: 364
Datum
2012
Autor:innen
Richet, Emma
Pooler, Amy M.
Rodriguez, Teresa
Novoselov, Sergey S.
Hanger, Diane P.
Cheetham, Michael E.
Spuy, Jacqueline van der
Herausgeber:innen
Kontakt
ISSN der Zeitschrift
Electronic ISSN
ISBN
Bibliografische Daten
Verlag
Schriftenreihe
Auflagebezeichnung
DOI (zitierfähiger Link)
ArXiv-ID
Internationale Patentnummer
Angaben zur Forschungsförderung
Projekt
Open Access-Veröffentlichung
Open Access Green
Sammlungen
Core Facility der Universität Konstanz
Gesperrt bis
Titel in einer weiteren Sprache
Publikationstyp
Zeitschriftenartikel
Publikationsstatus
Published
Erschienen in
Human Molecular Genetics. 2012, 21(24), pp. 5254-5267. ISSN 0964-6906. eISSN 1460-2083. Available under: doi: 10.1093/hmg/dds376
Zusammenfassung

Abnormal phosphorylation of the microtubule-associated protein tau in neurodegenerative disorders, including Alzheimer’s disease (AD) and frontotemporal lobar degeneration, is associated with disrupted axonal transport and synaptic dysfunction ultimately manifesting as histopathological lesions of protein aggregates. Glycogen synthase kinase 3b (GSK3b) may be critical for the pathological hyperphosphorylation of tau. Here, we examined the role of the proteasome-associated protein Nedd8 ultimate buster 1 (NUB1) in the neuropathogenic phosphorylation and aggregation of tau. We reveal that NUB1 interacted with both tau and GSK3b to disrupt their interaction, and abolished recruitment of GSK3b to tau inclusions. Moreover, NUB1 reduced GSK3b-mediated phosphorylation of tau and aggregation of tau in intracellular inclusions. Strikingly, NUB1 induced GSK3b degradation. Deletion of the NUB1 ubiquitin-like (UBL) domain did not impair the interaction with tau and GSK3b, and the ability to suppress the phosphorylation and aggregation of tau was not affected. However, the UBL motif was necessary for GSK3b degradation. Deletion of the NUB1 ubiquitin-associated (UBA) domain abrogated the ability of NUB1 to interact with and degrade GSK3b. Moreover, the UBA domain was required to suppress the aggregation of tau. Silencing of NUB1 in cells stabilized endogenous GSK3b and exacerbated tau phosphorylation. Thus, we propose that NUB1, by regulating GSK3b levels, modulates tau phosphorylation and aggregation, and is a key player in neurodegeneration associated with tau pathology. Moreover, NUB1 regulation of GSK3b could modulate numerous signalling pathways in which GSK3b is a centrally important effector.

Zusammenfassung in einer weiteren Sprache
Fachgebiet (DDC)
570 Biowissenschaften, Biologie
Schlagwörter
Konferenz
Rezension
undefined / . - undefined, undefined
Forschungsvorhaben
Organisationseinheiten
Zeitschriftenheft
Datensätze
Zitieren
ISO 690RICHET, Emma, Amy M. POOLER, Teresa RODRIGUEZ, Sergey S. NOVOSELOV, Gunter SCHMIDTKE, Marcus GRÖTTRUP, Diane P. HANGER, Michael E. CHEETHAM, Jacqueline van der SPUY, 2012. NUB1 modulation of GSK3β reduces tau aggregation. In: Human Molecular Genetics. 2012, 21(24), pp. 5254-5267. ISSN 0964-6906. eISSN 1460-2083. Available under: doi: 10.1093/hmg/dds376
BibTex
@article{Richet2012-12-15modul-21991,
  year={2012},
  doi={10.1093/hmg/dds376},
  title={NUB1 modulation of GSK3β reduces tau aggregation},
  number={24},
  volume={21},
  issn={0964-6906},
  journal={Human Molecular Genetics},
  pages={5254--5267},
  author={Richet, Emma and Pooler, Amy M. and Rodriguez, Teresa and Novoselov, Sergey S. and Schmidtke, Gunter and Gröttrup, Marcus and Hanger, Diane P. and Cheetham, Michael E. and Spuy, Jacqueline van der}
}
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/123456789/21991">
    <dc:creator>Pooler, Amy M.</dc:creator>
    <dc:contributor>Novoselov, Sergey S.</dc:contributor>
    <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2013-02-22T08:29:17Z</dc:date>
    <dc:contributor>Richet, Emma</dc:contributor>
    <dspace:hasBitstream rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/21991/2/Richet_219910.pdf"/>
    <dc:creator>Gröttrup, Marcus</dc:creator>
    <dc:contributor>Pooler, Amy M.</dc:contributor>
    <dc:creator>Cheetham, Michael E.</dc:creator>
    <dcterms:issued>2012-12-15</dcterms:issued>
    <dcterms:abstract xml:lang="eng">Abnormal phosphorylation of the microtubule-associated protein tau in neurodegenerative disorders, including Alzheimer’s disease (AD) and frontotemporal lobar degeneration, is associated with disrupted axonal transport and synaptic dysfunction ultimately manifesting as histopathological lesions of protein aggregates. Glycogen synthase kinase 3b (GSK3b) may be critical for the pathological hyperphosphorylation of tau. Here, we examined the role of the proteasome-associated protein Nedd8 ultimate buster 1 (NUB1) in the neuropathogenic phosphorylation and aggregation of tau. We reveal that NUB1 interacted with both tau and GSK3b to disrupt their interaction, and abolished recruitment of GSK3b to tau inclusions. Moreover, NUB1 reduced GSK3b-mediated phosphorylation of tau and aggregation of tau in intracellular inclusions. Strikingly, NUB1 induced GSK3b degradation. Deletion of the NUB1 ubiquitin-like (UBL) domain did not impair the interaction with tau and GSK3b, and the ability to suppress the phosphorylation and aggregation of tau was not affected. However, the UBL motif was necessary for GSK3b degradation. Deletion of the NUB1 ubiquitin-associated (UBA) domain abrogated the ability of NUB1 to interact with and degrade GSK3b. Moreover, the UBA domain was required to suppress the aggregation of tau. Silencing of NUB1 in cells stabilized endogenous GSK3b and exacerbated tau phosphorylation. Thus, we propose that NUB1, by regulating GSK3b levels, modulates tau phosphorylation and aggregation, and is a key player in neurodegeneration associated with tau pathology. Moreover, NUB1 regulation of GSK3b could modulate numerous signalling pathways in which GSK3b is a centrally important effector.</dcterms:abstract>
    <dcterms:isPartOf rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/28"/>
    <dc:language>eng</dc:language>
    <dc:contributor>Hanger, Diane P.</dc:contributor>
    <dc:creator>Spuy, Jacqueline van der</dc:creator>
    <dcterms:hasPart rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/21991/2/Richet_219910.pdf"/>
    <dspace:isPartOfCollection rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/28"/>
    <dcterms:rights rdf:resource="https://rightsstatements.org/page/InC/1.0/"/>
    <dc:creator>Richet, Emma</dc:creator>
    <dc:contributor>Schmidtke, Gunter</dc:contributor>
    <dc:creator>Schmidtke, Gunter</dc:creator>
    <dc:contributor>Spuy, Jacqueline van der</dc:contributor>
    <foaf:homepage rdf:resource="http://localhost:8080/"/>
    <bibo:uri rdf:resource="http://kops.uni-konstanz.de/handle/123456789/21991"/>
    <dc:creator>Rodriguez, Teresa</dc:creator>
    <dcterms:available rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2013-02-22T08:29:17Z</dcterms:available>
    <dc:contributor>Gröttrup, Marcus</dc:contributor>
    <dc:contributor>Cheetham, Michael E.</dc:contributor>
    <dcterms:title>NUB1 modulation of GSK3β reduces tau aggregation</dcterms:title>
    <dc:creator>Novoselov, Sergey S.</dc:creator>
    <dc:contributor>Rodriguez, Teresa</dc:contributor>
    <dc:creator>Hanger, Diane P.</dc:creator>
    <dcterms:bibliographicCitation>Human Molecular Genetics ; 21 (2012), 24. - S. 5254-5267</dcterms:bibliographicCitation>
    <dc:rights>terms-of-use</dc:rights>
    <void:sparqlEndpoint rdf:resource="http://localhost/fuseki/dspace/sparql"/>
  </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
Diese Publikation teilen