Repository logo
 

Proliferation of Tau 304-380 Fragment Aggregates through Autocatalytic Secondary Nucleation.

Simple item page
cam.issuedOnline2021-11-16
dc.contributor.authorRodriguez Camargo, Diana C
dc.contributor.authorSileikis, Eimantas
dc.contributor.authorChia, Sean
dc.contributor.authorAxell, Emil
dc.contributor.authorBernfur, Katja
dc.contributor.authorCataldi, Rodrigo L
dc.contributor.authorCohen, Samuel IA
dc.contributor.authorMeisl, Georg
dc.contributor.authorHabchi, Johnny
dc.contributor.authorKnowles, Tuomas PJ
dc.contributor.authorVendruscolo, Michele
dc.contributor.authorLinse, Sara
dc.contributor.orcidMeisl, Georg [0000-0002-6562-7715]
dc.contributor.orcidKnowles, Tuomas PJ [0000-0002-7879-0140]
dc.contributor.orcidVendruscolo, Michele [0000-0002-3616-1610]
dc.contributor.orcidLinse, Sara [0000-0001-9629-7109]
dc.date.accessioned2022-01-07T16:49:56Z
dc.date.available2022-01-07T16:49:56Z
dc.date.issued2021-12-01
dc.date.updated2022-01-07T16:49:55Z
dc.description.abstractThe self-assembly of the protein tau into neurofibrillary tangles is one of the hallmarks of Alzheimer's disease and related tauopathies. Still, the molecular mechanism of tau aggregation is largely unknown. This problem may be addressed by systematically obtaining reproducible in vitro kinetics measurements under quiescent conditions in the absence of triggering substances. Here, we implement this strategy by developing protocols for obtaining an ultrapure tau fragment (residues 304-380 of tau441) and for performing spontaneous aggregation assays with reproducible kinetics under quiescent conditions. We are thus able to identify the mechanism of fibril formation of the tau 304-380 fragment at physiological pH using fluorescence spectroscopy and mass spectrometry. We find that primary nucleation is slow, and that secondary processes dominate the aggregation process once the initial aggregates are formed. Moreover, our results further show that secondary nucleation of monomers on fibril surfaces dominates over fragmentation of fibrils. Using separate isotopes in monomers and fibrils, through mass spectroscopy measurements, we verify the isotope composition of the intermediate oligomeric species, which reveals that these small aggregates are generated from monomer through secondary nucleation. Our results provide a framework for understanding the processes leading to tau aggregation in disease and for selecting possible tau forms as targets in the development of therapeutic interventions in Alzheimer's disease.
dc.identifier.doi10.17863/CAM.79819
dc.identifier.eissn1948-7193
dc.identifier.issn1948-7193
dc.identifier.otherPMC8640994
dc.identifier.other34783519
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/332373
dc.languageeng
dc.language.isoeng
dc.publisherAmerican Chemical Society (ACS)
dc.publisher.urlhttp://dx.doi.org/10.1021/acschemneuro.1c00454
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceessn: 1948-7193
dc.sourcenlmid: 101525337
dc.subjectfolding unit
dc.subjectintracellular aggregation
dc.subjectprecipitation
dc.subjectself-association
dc.subjectsurface catalysis
dc.subjecttubulin-associated unit
dc.subjectAlzheimer Disease
dc.subjectCell Proliferation
dc.subjectHumans
dc.subjectKinetics
dc.subjectNeurofibrillary Tangles
dc.subjectProtein Aggregates
dc.subjecttau Proteins
dc.titleProliferation of Tau 304-380 Fragment Aggregates through Autocatalytic Secondary Nucleation.
dc.typeArticle
prism.endingPage4415
prism.issueIdentifier23
prism.publicationNameACS Chem Neurosci
prism.startingPage4406
prism.volume12
pubs.funder-project-idVetenskapsr??det (2015-00143)
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1021/acschemneuro.1c00454

Files

Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
article.pdf
Size:
14.77 MB
Format:
Adobe Portable Document Format
Description:
Published version
Licence
https://creativecommons.org/licenses/by/4.0/
Download

Collections

Jisc Publications Router