Protein aggregation into insoluble deposits protects from oxidative stress

Abstract

Protein misfolding and aggregation have been associated with the onset of neurodegenerative disorders. Recent studies demonstrate that the aggregation process can result in a high diversity of protein conformational states, however the identity of the specific species responsible for the cellular damage is still unclear. Here, we use yeast as a model to systematically analyse the intracellular effect of expressing 21 variants of the amyloid-ß-peptide, engineered to cover a continuous range of intrinsic aggregation propensities. We demonstrate the existence of a striking negative correlation between the aggregation propensity of a given variant and the oxidative stress it elicits. Interestingly, each variant generates a specific distribution of protein assemblies in the cell. This allowed us to identify the aggregated species that remain diffusely distributed in the cytosol and are unable to coalesce into large protein inclusions as those causing the highest levels of oxidative damage. Overall, our results indicate that the formation of large insoluble aggregates may act as a protective mechanism to avoid cellular oxidative stress.

Bioprospection of Natural Sources of Polyphenols with Therapeutic Potential for Redox-Related Diseases

“…Mechanistic studies were performed and suggest that R. genevieri (poly)phenolics led FUS to be trapped into insoluble intracellular structures thereby reducing its pathological activity. This is a well-known route of cellular protection against the toxic effect of several oligomerization-prone proteins described for several diseases [ 40 ]. It remains to identify the major molecular players in this process and to evaluate whether this mechanism is conserved in higher eukaryotes.…”

Cross-talk between redox signalling and protein aggregation

“…Redox signalling-dependent protein oxidation could, therefore, be a facilitator of aggregation and actually partake in the proteotoxic stress response. In support of this, it was shown that promoting the formation of large insoluble aggregates is protective against amyloid-induced ROS production [112].…”

Glutathionylation primes soluble glyceraldehyde-3-phosphate dehydrogenase for late collapse into insoluble aggregates

“…have been shown to favor protein aggregation, presumably by lowering the energy barriers separating native from misfolded conformations (18)(19)(20)(21). Although, in some cases, nonamyloid protein aggregation can induce cell death (22,23), protein aggregation may also be beneficial to cells as long as sequestration of aggregates in specific cell sites prevents toxicity (24). Indeed, nonamyloid protein aggregates may be asymmetrically inherited by daughter cells (25), dissolved by chaperones (12,26), or digested by proteases (27) or autophagy (28,29).…”