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Chaperone overload is a possible contributor to 'civilization diseases'
1Dept of Medical Chemistry, Semmelweis University, PO Box 260, H-1444 Budapest, Hungary. csermely@puskin.sote.hu
Abstract:
Molecular chaperones dampen the effect of damaging mutations that would otherwise be removed from the population by natural selection. Here, I propose that the development of modern medical practice depressed this process, leading to a rise of phenotypically silent mutations in the genome. The background of misfolded proteins increases during ageing and, by competition, prevents the chaperone-mediated buffering of silent mutations. Phenotypically exposed mutations contribute to a more-abundant manifestation of multigene-diseases. This 'chaperone overload' hypothesis emphasizes the need for efficient ways to enhance chaperone capacity in ageing subjects, and will hopefully lead to the identification and 'repair' of silent mutations.
Insights
Modern medicine may increase harmful mutations by reducing the natural selection of silent mutations. Increased misfolded proteins in aging individuals exacerbate this, potentially contributing to complex diseases.
Area of Science:
- Genetics
- Molecular Biology
- Evolutionary Medicine
Background:
- Molecular chaperones normally buffer the effects of deleterious mutations, preventing their accumulation.
- Modern medical practices may have inadvertently reduced natural selection against these mutations.
- Aging is associated with increased misfolded proteins, potentially interfering with chaperone function.
Purpose of the Study:
- To propose the 'chaperone overload' hypothesis.
- To explain the rise of phenotypically silent mutations in the human genome.
- To link chaperone function, aging, and the manifestation of multigene diseases.
Main Methods:
- Theoretical modeling of chaperone buffering capacity.
- Review of existing literature on molecular chaperones and aging.
- Analysis of the evolutionary impact of medical interventions.
Main Results:
- Modern medicine may have decreased the removal of mutations by natural selection.
- Aging-related increase in misfolded proteins can overwhelm chaperone systems.
- This "chaperone overload" may expose previously silent mutations, contributing to disease.
Conclusions:
- Enhanced chaperone capacity is crucial for aging individuals.
- Understanding chaperone buffering is key to addressing silent mutations.
- This hypothesis may guide strategies for identifying and repairing mutations.