NUB1 modulation of GSK3β reduces tau aggregation


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RICHET, 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. 21(24), pp. 5254-5267. ISSN 0964-6906. eISSN 1460-2083. Available under: doi: 10.1093/hmg/dds376

@article{Richet2012-12-15modul-21991, title={NUB1 modulation of GSK3β reduces tau aggregation}, year={2012}, doi={10.1093/hmg/dds376}, 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 xmlns:dcterms="" xmlns:dc="" xmlns:rdf="" xmlns:bibo="" xmlns:dspace="" xmlns:foaf="" xmlns:void="" xmlns:xsd="" > <rdf:Description rdf:about=""> <dcterms:hasPart rdf:resource=""/> <dc:contributor>Spuy, Jacqueline van der</dc:contributor> <dc:creator>Hanger, Diane P.</dc:creator> <dcterms:title>NUB1 modulation of GSK3β reduces tau aggregation</dcterms:title> <dc:rights>terms-of-use</dc:rights> <dc:creator>Gröttrup, Marcus</dc:creator> <dc:contributor>Hanger, Diane P.</dc:contributor> <dc:language>eng</dc:language> <dc:creator>Richet, Emma</dc:creator> <dc:contributor>Richet, Emma</dc:contributor> <dc:creator>Novoselov, Sergey S.</dc:creator> <dc:contributor>Schmidtke, Gunter</dc:contributor> <dspace:isPartOfCollection rdf:resource=""/> <void:sparqlEndpoint rdf:resource="http://localhost/fuseki/dspace/sparql"/> <dc:creator>Rodriguez, Teresa</dc:creator> <dc:creator>Spuy, Jacqueline van der</dc:creator> <dcterms:issued>2012-12-15</dcterms:issued> <dc:creator>Schmidtke, Gunter</dc:creator> <dc:creator>Pooler, Amy M.</dc:creator> <dc:contributor>Rodriguez, Teresa</dc:contributor> <bibo:uri rdf:resource=""/> <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:available rdf:datatype="">2013-02-22T08:29:17Z</dcterms:available> <dc:contributor>Novoselov, Sergey S.</dc:contributor> <dc:date rdf:datatype="">2013-02-22T08:29:17Z</dc:date> <dc:contributor>Gröttrup, Marcus</dc:contributor> <dcterms:isPartOf rdf:resource=""/> <dspace:hasBitstream rdf:resource=""/> <dc:creator>Cheetham, Michael E.</dc:creator> <foaf:homepage rdf:resource="http://localhost:8080/jspui"/> <dc:contributor>Cheetham, Michael E.</dc:contributor> <dcterms:bibliographicCitation>Human Molecular Genetics ; 21 (2012), 24. - S. 5254-5267</dcterms:bibliographicCitation> <dc:contributor>Pooler, Amy M.</dc:contributor> <dcterms:rights rdf:resource=""/> </rdf:Description> </rdf:RDF>

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