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Protein aggregation into insoluble deposits protects from oxidative stress
Anita Carija1, Susanna Navarro1, Natalia Sanchez de Groot2
1Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.
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.
Insights
Protein aggregation in neurodegenerative diseases is complex. Small, diffusely distributed protein assemblies, not large inclusions, cause the most oxidative stress, suggesting large aggregates may be protective.
Area of Science:
- Neuroscience
- Biochemistry
- Cell Biology
Background:
- Protein misfolding and aggregation are linked to neurodegenerative diseases.
- The specific protein species causing cellular damage remain unclear.
- Diverse protein conformational states arise during aggregation.
Purpose of the Study:
- To investigate the intracellular effects of amyloid-beta peptide variants with varying aggregation propensities.
- To identify which protein species are responsible for cellular damage and oxidative stress.
Main Methods:
- Utilized yeast as a model organism.
- Systematically analyzed 21 engineered amyloid-beta peptide variants.
- Quantified intracellular oxidative stress elicited by each variant.
Main Results:
- A negative correlation was observed between aggregation propensity and elicited oxidative stress.
- Each variant produced a distinct distribution of protein assemblies within the cell.
- Diffusely distributed cytosolic assemblies, unable to form large inclusions, caused the highest oxidative damage.
Conclusions:
- Large, insoluble protein aggregates may serve as a protective mechanism against cellular oxidative stress.
- The physical state and distribution of protein aggregates are critical determinants of cellular toxicity.
- Understanding these species-specific effects is crucial for developing therapeutic strategies for neurodegenerative disorders.