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Evidence for the existence of a secondary pathway for fibril growth during the aggregation of tau.

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TitleEvidence for the existence of a secondary pathway for fibril growth during the aggregation of tau.
Publication TypeJournal Article
Year of Publication2012
AuthorsRamachandran G, Udgaonkar JB
JournalJ Mol Biol
Volume421
Issue2-3
Pagination296-314
Date Published2012 Aug 10
ISSN1089-8638
KeywordsAmyloid, Kinetics, Micelles, Microscopy, Atomic Force, Models, Chemical, tau Proteins
Abstract

The mechanism of amyloid fibril formation by proteins has been classically described by the nucleation-dependent polymerization (NDP) model, which makes certain predictions regarding the kinetics of fibrillation. All proteins whose aggregation conforms to the NDP model display a t(2) time dependence for their initial reaction profile. However, there are proteins whose aggregation reactions have kinetic signatures of a flat lag phase followed by an exponential rise in fibril mass, which does not conform to the NDP model. Amyloid fibril formation by tau, a microtubule-associated protein whose aggregation to form neurofibrillary tangles is implicated in Alzheimer's disease and other tauopathies, in the presence of inducers such as heparin and fatty acid micelles, has always been traditionally described by a ligand-induced NDP model. In this study, the existence of a secondary pathway for fibril growth during the aggregation of the functional, repeat domain of tau in the presence of heparin has been established. Both kinetic and accessory evidence are provided for the existence of this pathway, which is shown to augment the primary homogeneous nucleation pathway. From the kinetic data, the main secondary pathway that is operative appears to be fibril fragmentation but other pathways such as branching or secondary nucleation may also be operative.

DOI10.1016/j.jmb.2012.01.007
Alternate JournalJ. Mol. Biol.
PubMed ID22281439