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Oligomer Diversity during the Aggregation of the Repeat Region of Tau.

Abstract：

:The 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.

journal_name

ACS Chem Neurosci

journal_title

ACS chemical neuroscience

authors

Kjaergaard M,Dear AJ,Kundel F,Qamar S,Meisl G,Knowles TPJ,Klenerman D

doi

10.1021/acschemneuro.8b00250

subject

Has Abstract

pub_date

2018-12-19 00:00:00

pages

3060-3071

issue

issn

1948-7193

journal_volume

pub_type

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Oligomer Diversity during the Aggregation of the Repeat Region of Tau.