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Updated: Apr 30, 2026
Evaluation of the Impact of Protein Aggregation on Cellular Oxidative Stress in Yeast
Published on: June 23, 2018
Defining the limits: Protein aggregation and toxicity in vivo
William M Holmes1, Courtney L Klaips, Tricia R Serio
1Biology Department, College of the Holy Cross , Worcester, MA , USA and.
Abstract:
Abstract others complementary, to resolve mis-folded proteins when they arise, ranging from refolding through the action of molecular chaperones to elimination through regulated proteolytic mechanisms. These protein quality control pathways are sufficient, under normal conditions, to maintain a functioning proteome, but in response to diverse environmental, genetic and/or stochastic events, protein mis-folding exceeds the corrective capacity of these pathways, leading to the accumulation of aggregates and ultimately toxicity. Particularly devastating examples of these effects include certain neurodegenerative diseases, such as Huntington's Disease, which are associated with the expansion of polyglutamine tracks in proteins. In these cases, protein mis-folding and aggregation are clear contributors to pathogenesis, but uncovering the precise mechanistic links between the two events remains an area of active research. Studies in the yeast Saccharomyces cerevisiae and other model systems have uncovered previously unanticipated complexity in aggregation pathways, the contributions of protein quality control processes to them and the cellular perturbations that result from them. Together these studies suggest that aggregate interactions and localization, rather than their size, are the crucial considerations in understanding the molecular basis of toxicity.
Insights
Cellular protein quality control pathways manage misfolded proteins but can be overwhelmed, leading to toxic aggregates. Aggregate interactions and location, not size, are key to understanding toxicity in diseases like Huntington's.
Area of Science:
- Molecular Biology
- Cell Biology
- Neuroscience
Background:
- Cellular protein quality control (PQC) mechanisms, including molecular chaperones and proteolytic degradation, normally maintain proteome homeostasis.
- Disruptions from environmental, genetic, or stochastic factors can overwhelm PQC, causing protein misfolding, aggregation, and cellular toxicity.
- Neurodegenerative diseases, such as Huntington's Disease, are linked to expanded polyglutamine tracts and protein aggregation, highlighting the need to understand these processes.
Purpose of the Study:
- To investigate the mechanistic links between protein misfolding, aggregation, and toxicity in the context of neurodegenerative diseases.
- To explore the complexity of protein aggregation pathways and the role of PQC processes in model systems.
- To determine the critical factors underlying the molecular basis of protein aggregate toxicity.
Main Methods:
- Utilized yeast (Saccharomyces cerevisiae) and other model systems to study protein aggregation pathways.
- Examined the interplay between protein quality control processes and aggregate formation.
- Analyzed cellular perturbations resulting from protein misfolding and aggregation.
Main Results:
- Uncovered significant complexity in protein aggregation pathways and their relationship with PQC.
- Demonstrated that cellular PQC pathways can be overwhelmed by protein misfolding events.
- Identified aggregate interactions and cellular localization as critical determinants of toxicity, rather than aggregate size.
Conclusions:
- Protein misfolding and aggregation are key contributors to pathogenesis in diseases like Huntington's Disease.
- Aggregate interactions and localization are more critical than aggregate size in determining molecular toxicity.
- Further research into these interactions and localization is essential for understanding neurodegenerative disease mechanisms.
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