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dc.contributor.authorMeng, Jonathan X
dc.contributor.authorZhang, Yu
dc.contributor.authorSaman, Dominik
dc.contributor.authorHaider, Arshad M
dc.contributor.authorDe, Suman
dc.contributor.authorSang, Jason C
dc.contributor.authorBrown, Karen
dc.contributor.authorJiang, Kun
dc.contributor.authorHumphrey, Jane
dc.contributor.authorJulian, Linda
dc.contributor.authorHidari, Eric
dc.contributor.authorLee, Steven F
dc.contributor.authorBalmus, Gabriel
dc.contributor.authorFloto, R Andres
dc.contributor.authorBryant, Clare
dc.contributor.authorBenesch, Justin LP
dc.contributor.authorYe, Yu
dc.contributor.authorKlenerman, David
dc.date.accessioned2022-05-16T16:00:51Z
dc.date.available2022-05-16T16:00:51Z
dc.date.issued2022-05-16
dc.date.submitted2021-04-08
dc.identifier.others41467-022-30461-x
dc.identifier.other30461
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/337194
dc.descriptionFunder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265
dc.descriptionFunder: Alzheimer's Society; doi: https://doi.org/10.13039/501100000320
dc.descriptionFunder: Alzheimer's Research UK (ARUK); doi: https://doi.org/10.13039/501100002283
dc.description.abstractAbstract: Soluble aggregates of the microtubule-associated protein tau have been challenging to assemble and characterize, despite their important role in the development of tauopathies. We found that sequential hyperphosphorylation by protein kinase A in conjugation with either glycogen synthase kinase 3β or stress activated protein kinase 4 enabled recombinant wild-type tau of isoform 0N4R to spontaneously polymerize into small amorphous aggregates in vitro. We employed tandem mass spectrometry to determine the phosphorylation sites, high-resolution native mass spectrometry to measure the degree of phosphorylation, and super-resolution microscopy and electron microscopy to characterize the morphology of aggregates formed. Functionally, compared with the unmodified aggregates, which require heparin induction to assemble, these self-assembled hyperphosphorylated tau aggregates more efficiently disrupt membrane bilayers and induce Toll-like receptor 4-dependent responses in human macrophages. Together, our results demonstrate that hyperphosphorylated tau aggregates are potentially damaging to cells, suggesting a mechanism for how hyperphosphorylation could drive neuroinflammation in tauopathies.
dc.languageen
dc.publisherNature Publishing Group UK
dc.subjectArticle
dc.subject/631/92/458
dc.subject/631/1647/296
dc.subject/631/80/2373
dc.subject/631/57/2269
dc.subject/631/45/470/2284
dc.subject/9
dc.subject/82/58
dc.subject/14/34
dc.subject/38
dc.subject/38/77
dc.subject/96
dc.subject/96/21
dc.subjectarticle
dc.titleHyperphosphorylated tau self-assembles into amorphous aggregates eliciting TLR4-dependent responses
dc.typeArticle
dc.date.updated2022-05-16T16:00:51Z
prism.issueIdentifier1
prism.publicationNameNature Communications
prism.volume13
dc.identifier.doi10.17863/CAM.84612
dcterms.dateAccepted2022-04-28
rioxxterms.versionofrecord10.1038/s41467-022-30461-x
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidBryant, Clare [0000-0002-2924-0038]
dc.contributor.orcidKlenerman, David [0000-0001-7116-6954]
dc.identifier.eissn2041-1723
pubs.funder-project-idRoyal Society (RP150066)


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