Show simple item record

dc.contributor.authorKjaergaard, Magnus
dc.contributor.authorDear, Alexander J
dc.contributor.authorKundel, Franziska
dc.contributor.authorQamar, Seema
dc.contributor.authorMeisl, Georg
dc.contributor.authorKnowles, Tuomas PJ
dc.contributor.authorKlenerman, David
dc.description.abstractThe molecular mechanism of protein aggregation is of both fundamental and clinical importance as amyloid aggregates are linked to a number of neurodegenerative disorders. Such protein aggregates include macroscopic insoluble fibrils as well as small soluble oligomeric species. Time-dependent resolution of these species is prerequisite for a detailed quantitative understanding of protein aggregation; this remains challenging due to the lack of methods for detecting and characterizing transient and heterogeneous protein oligomers. Here we have used single molecule fluorescence techniques combined with mechanistic modeling to study the heparin-induced aggregation of the repeat region of tau, which forms the core region of neurofibrillary tangles found in Alzheimer's disease. We distinguish several subpopulations of oligomers with different stability and follow their evolution during aggregation reactions as a function of temperature and concentration. Employment of techniques from chemical kinetics reveals that the two largest populations are structurally distinct from fibrils and are both kinetically and thermodynamically unstable. The first population is in rapid exchange with monomers and held together by electrostatic interactions; the second is kinetically more stable, dominates at later times, and is probably off-pathway to fibril formation. These more stable oligomers may contribute to other oligomer induced effects in the cellular environment, for example, by overloading protein quality control systems. We also show that the shortest growing filaments remain suspended in aqueous buffer and thus comprise a third, smaller population of transient oligomers with cross-β structure. Overall our data show that a diverse population of oligomers of different structures and half-lives are formed during the aggregation reaction with the great majority of oligomers formed not going on to form fibrils.
dc.description.sponsorshipDK acknowledges funding from the Royal Society and ERC Advanced Grant (669237). MK acknowledges fellowships from the Danish Research Council and the Lundbeck Foundation (R165-2013-15269). AJD acknowledges a studentship from the Schiff Foundation. GM acknowledges a fellowship from Sidney Sussex College, Cambridge. TPJK acknowledges financial support from the Wellcome Trust, the Cambridge Centre for Misfolding Diseases, the BBSRC, and the Frances and Augustus Newman foundation. The research leading to these results has received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013) through the ERC grant PhysProt (agreement no. 337969).
dc.publisherAmerican Chemical Society (ACS)
dc.rightsAttribution 4.0 International
dc.subjectNeurofibrillary Tangles
dc.subjecttau Proteins
dc.subjectFluorescence Resonance Energy Transfer
dc.subjectGenes, Synthetic
dc.subjectModels, Molecular
dc.subjectAmyloid beta-Peptides
dc.subjectProtein Aggregation, Pathological
dc.subjectSingle Molecule Imaging
dc.titleOligomer Diversity during the Aggregation of the Repeat Region of Tau.
prism.publicationNameACS Chem Neurosci
dc.contributor.orcidKjaergaard, Magnus [0000-0002-7020-9366]
dc.contributor.orcidKundel, Franziska [0000-0001-5013-0004]
dc.contributor.orcidMeisl, Georg [0000-0002-6562-7715]
dc.contributor.orcidKnowles, Tuomas PJ [0000-0002-7879-0140]
rioxxterms.typeJournal Article/Review
pubs.funder-project-idEuropean Research Council (669237)
pubs.funder-project-idRoyal Society (RP150066)
pubs.funder-project-idBiotechnology and Biological Sciences Research Council (BB/J002119/1)
pubs.funder-project-idEuropean Research Council (337969)

Files in this item


This item appears in the following Collection(s)

Show simple item record

Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International