The role of annealing and fragmentation in human tau aggregation dynamics

Carol J. Huseby, Ralf Bundschuh, Jeff Kuret

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Alzheimer’s disease pathogenesis is associated with the conversion of monomeric tau protein into filamentous aggregates. Because both toxicity and prion-like spread of pathogenic tau depend in part on aggregate size, the processes that underlie filament formation and size distribution are of special importance. Here, using a combination of biophysical and computational approaches, we investigated the fibrillation dynamics of the human tau isoform 2N4R. We found that tau filaments engage in a previously uncharacterized secondary process involving end-to-end annealing and that rationalization of empirical aggregation data composed of total protomer concentrations and fibril length distributions requires inclusion of this process along with filament fragmentation. We noted that annealing of 2N4R tau filaments is robust, with an intrinsic association rate constant of a magnitude similar to that mediating monomer addition and consistent with diffusion-mediated protein–protein interactions in the absence of long-range attractive forces. In contrast, secondary nucleation on the surface of tau filaments did not detectably contribute to tau aggregation dynamics. These results indicate that tau filament ends engage in a range of homotypic interactions involving monomers, oligomers, and filaments. They further indicate that, in the case of tau protein, fibril annealing and fragmentation along with primary nucleation and elongation are the major processes controlling filament size distribution.

Original languageEnglish (US)
Pages (from-to)4728-4737
Number of pages10
JournalJournal of Biological Chemistry
Volume294
Issue number13
DOIs
StatePublished - Mar 29 2019
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'The role of annealing and fragmentation in human tau aggregation dynamics'. Together they form a unique fingerprint.

Cite this