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Shape matters: the complex relationship between aggregation and toxicity in protein-misfolding diseases
Heidrun Maja Ries1, Carmen Nussbaum-Krammer2
1Center for Molecular Biology of Heidelberg University (ZMBH) and German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg 69120, Germany.
Abstract:
A particular subgroup of protein-misfolding diseases, comprising Alzheimer's and Parkinson's disease, involves amyloidogenic proteins that can form alternative pathogenic conformations with a high tendency to self-assemble into oligomeric and fibrillar species. Although misfolded proteins have been clearly linked to disease, the exact nature of the toxic species remains highly controversial. Increasing evidence suggests that there is little correlation between the occurrence of macroscopic protein deposits and toxic phenotypes in affected cells and tissues. In this article, we recap amyloid aggregation pathways, describe prion-like propagation, elaborate on detrimental interactions of protein aggregates with the cellular protein quality control system and discuss why some aggregates are toxic, whereas others seem to be beneficial. On the basis of recent studies on prion strains, we reason that the specific aggregate conformation and the resulting individual interaction with the cellular environment might be the major determinant of toxicity.
Insights
Misfolded proteins in neurodegenerative diseases like Alzheimer's can form toxic aggregates. The specific shape of these protein aggregates, not just their presence, likely determines disease toxicity and cellular interactions.
Area of Science:
- Neurodegenerative diseases
- Protein misfolding and aggregation
- Cellular protein quality control
Background:
- Alzheimer's and Parkinson's diseases are linked to amyloidogenic proteins forming pathogenic conformations.
- The exact toxic species in protein-misfolding diseases remain controversial.
- Macroscopic protein deposits often show little correlation with cellular toxicity.
Purpose of the Study:
- To review amyloid aggregation pathways and prion-like propagation.
- To elaborate on the interactions between protein aggregates and cellular quality control systems.
- To discuss the determinants of aggregate toxicity versus beneficial effects.
Main Methods:
- Review of existing literature on amyloid aggregation and prion strains.
- Analysis of detrimental interactions between protein aggregates and cellular systems.
- Reasoning based on prion strain studies to determine toxicity factors.
Main Results:
- Misfolded proteins can adopt various pathogenic conformations leading to self-assembly.
- Protein aggregates interact detrimentally with cellular protein quality control mechanisms.
- Aggregate conformation, not just presence, influences toxicity.
Conclusions:
- The specific conformation of protein aggregates is a key factor in their toxicity.
- Individual aggregate interactions with the cellular environment dictate pathogenic outcomes.
- Understanding aggregate conformation is crucial for deciphering neurodegenerative disease mechanisms.
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