Variations in filament conformation dictate seeding barrier between three- and four-repeat tau - PubMed (original) (raw)

. 2011 May 24;50(20):4330-6.

doi: 10.1021/bi2004685. Epub 2011 May 2.

Affiliations

Variations in filament conformation dictate seeding barrier between three- and four-repeat tau

Paul D Dinkel et al. Biochemistry. 2011.

Abstract

Tau filaments are the pathological hallmark of >20 neurodegenerative diseases including Alzheimer's disease. Six tau isoforms exist that can be grouped into 4-repeat (4R) tau and 3-repeat (3R) tau based on the presence or absence of the second of four microtubule binding repeats. Recent evidence suggests that tau filaments can transfer between cells and spread through the brain. Here we demonstrate in vitro that seeded filament growth, a prerequisite for tau spreading, is crucially dependent on the isoform composition of individual seeds. Seeds of 3R tau and 3R/4R tau recruit both types of isoforms. Seeds of 4R tau recruit 4R tau, but not 3R tau, establishing an asymmetric barrier. Conformational templating of 4R tau onto 3R tau seeds eliminates this barrier, giving rise to a new type of tau filament. These findings provide fundamental mechanistic insights into the seeding, propagation, and diversification of tau filaments.

PubMed Disclaimer

Similar articles

Cited by

Publication types

MeSH terms

Substances

LinkOut - more resources