Cross-talk between redox signalling and protein aggregation.

Loes Van Dam,Tobias B Dansen

doi:10.1042/bst20190054

Abstract

It is well established that both an increase in reactive oxygen species (ROS: i.e. O2•−, H2O2 and OH•), as well as protein aggregation, accompany ageing and proteinopathies such as Parkinson's and Alzheimer's disease. However, it is far from clear whether there is a causal relation between the two. This review describes how protein aggregation can be affected both by redox signalling (downstream of H2O2), as well as by ROS-induced damage, and aims to give an overview of the current knowledge of how redox signalling affects protein aggregation and vice versa. Redox signalling has been shown to play roles in almost every step of protein aggregation and amyloid formation, from aggregation initiation to the rapid oligomerization of large amyloids, which tend to be less toxic than oligomeric prefibrillar aggregates. We explore the hypothesis that age-associated elevated ROS production could be part of a redox signalling-dependent-stress response in an attempt to curb protein aggregation and minimize toxicity.

Highlights

Both the loss of proteostasis and reactive oxygen species (ROS) production as a consequence of mitochondrial dysfunction are among the Hallmarks of Ageing [1]
While at lower levels hydrogen peroxide (H2O2) acts as a second messenger in redox signalling, which is absolutely required for physiology and for lifespan extension in model systems [2], at higher levels H2O2 and other ROS could lead to random damage including for instance protein unfolding and aggregation, and the latter has been proposed to accelerate the aging process [3,4,5,6,7,8,9,10]
We have discussed the reciprocal regulation of redox signalling and protein aggregation

Summary

Introduction

Both the loss of proteostasis and ROS production as a consequence of mitochondrial dysfunction are among the Hallmarks of Ageing [1]. Oxidation of cysteines in proteins commonly causes structural changes and functional interactions through disulfide bond formation, such as (hetero)dimerization, oligomerization, and even aggregation, and thereby provides an important molecular switch for protein activity or function. We will focus mostly on the effects of reversible cysteine oxidation-dependent redox signalling but will include examples of how random oxidative damage affects protein aggregation.

Results

Conclusion