Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging
Open accessAbstract
The long-term health of the cell is inextricably linked to protein quality control. Under optimal conditions this is accomplished by protein homeostasis, a highly complex network of molecular interactions that balances protein biosynthesis, folding, translocation, assembly/disassembly, and clearance. This review will examine the consequences of an imbalance in homeostasis on the flux of misfolded proteins that, if unattended, can result in severe molecular damage to the cell. Adaptation and survival requires the ability to sense damaged proteins and to coordinate the activities of protective stress response pathways and chaperone networks. Yet, despite the abundance and apparent capacity of chaperones and other components of homeostasis to restore folding equilibrium, the cell appears poorly adapted for chronic proteotoxic stress when conformationally challenged aggregation-prone proteins are expressed in cancer, metabolic disease, and neurodegenerative disease. The decline in biosynthetic and repair activities that compromises the integrity of the proteome is influenced strongly by genes that control aging, thus linking stress and protein homeostasis with the health and life span of the organism.
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Aging-associated expression changes in genes associated with mitochondrial function, protein metabolism, and immune response have been identified in several tissues and are consistent with some proposed mechanisms for late-onset neurodegenerative diseases.
“Aging-associated expression changes in genes associated with mitochondrial function, protein metabolism, and immune response have been identified in several tissues (173) and are consistent with some proposed mechanisms for late-onset neurodegenerative diseases (98, 113, 124, 166).”
From Unraveling a Multifactorial Late-Onset Disease: From Genetic Susceptibility to Disease Mechanisms for Age-Related Macular Degeneration (2009) · cites this paper as [113]
Aging-associated decline in chaperone networks and protein degradation systems can lead to protein aggregates that compromise biochemical functions and cellular health.
“aging-associated decline in these pathways can lead to protein aggregates that can compromise biochemical functions and cellular health (113, 124).”
From Unraveling a Multifactorial Late-Onset Disease: From Genetic Susceptibility to Disease Mechanisms for Age-Related Macular Degeneration (2009) · cites this paper as [113]
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- Authors
- Morimoto, R. I.
- Affiliations
- Northwestern University (US)
- Corresponding author
- Morimoto, Richard I.
- ORCID
- Morimoto, Richard I.
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2008-06-01
- Volume
- 22
- Issue
- 11
- Pages
- 1427-1438
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC2732416
- OpenAlex
- W2132296982
- Cited by
- 872
- References
- 127
- Citations by year
- 2026: 22 · 2025: 20 · 2024: 18 · 2023: 20 · 2022: 28 · 2021: 35 · 2020: 29 · 2019: 41 · 2018: 32 · 2017: 44 · 2016: 47 · 2015: 70 · 2014: 80 · 2013: 75 · 2012: 62
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- ALS Association
- National Institutes of Health
- National Institute on Aging
- National Institute of General Medical Sciences
- National Institute of Neurological Disorders and Stroke
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Keywords
- proteotoxic stress, proteostasis, chaperone network, neurodegenerative diseases, aging, protein misfolding, protein aggregation, stress response pathways, cancer, metabolic disorders, lifespan
- MeSH terms
- Aging, Animals, Forecasting, Heat-Shock Proteins, Humans, Models, Biological, Protein Conformation, Protein Folding, Molecular Chaperones, Neurodegenerative Diseases, Proteomics
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