Flipping the switch: How cysteine oxidation directs tau amyloid conformations

Danny M Hatters

doi:10.1016/j.jbc.2021.101309

Abstract

Tau can adopt distinct fibril conformations in different human neurodegenerative diseases, which may invoke distinct pathological mechanisms. In a recent issue, Weismiller et al. showed that intramolecular disulfide links between cys291 and cys322 for a specific tau isoform containing four microtubule-binding repeats direct the formation of a structurally distinct amyloid polymorph. These findings have implications in how oxidative stress can flip switches of tau polymorphism in these diseases.

Highlights

One of the intriguing features of tau aggregates is that they can act like prions in propagating new deposits [2]
Prior studies have suggested that these cysteines play critical roles in modulating fibril assembly and in stabilizing monomer and dimer conformations [8, 9]; there was conflicting data as to whether intramolecular disulfide linkage facilitated or hindered the aggregation of tau monomers or dimers
Weismiller et al sought to address the specific question of how intramolecular disulfide bonds within tau affected the aggregation of the full length htau40 isoform

Summary

Introduction

One of the intriguing features of tau aggregates is that they can act like prions in propagating new deposits [2]. Weismiller et al [7] examine the effect of cysteine oxidation state on fibril assembly. The largest isoform of tau, which was the focus of this study, contains four microtubule-binding domain repeats (htau40) and is 441 amino acids in length.

Results

Conclusion