Protein aggregation into insoluble deposits protects from oxidative stress

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.
Graphical abstract fx1 The scheme represents three different scenarios that can occur in a yeast cell upon Aβ42-GFP peptide expression. Scenario I: Soluble Aβ42-GFP species that neither form protein inclusions, nor diffuse aggregates, are not dangerous for the cell; Scenario II: Aβ42-GFP species that do not form protein inclusions but form diffuse aggregates, which can cause intracellular oxidative stress, are hazardous for the cell; Scenario III: Aβ42-GFP species that form protein inclusions are not deleterious for the cell, suggesting that the formation of these big aggregates acts as a protective strategy against oxidative stress.
Highlights • Aβ42 peptides aggregation propensity negatively correlates with intracellular oxidative stress. • Low aggregation propensity Aβ42 variants accumulate as cytosolic diffuse aggregates instead of protein inclusions. • Diffuse aggregates are the major elicitors of oxidative stress. • Protein inclusion formation is a protective strategy against oxidative damage.