Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging.

By Richard I. Morimoto. Genes & Development, 2008

933 citations recorded by the source corpus.

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.

Subfields: Aging, Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/40a03ae2d0c8961a7c211f2bff2266588eb9b7ed

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Citations in the corpus

Tar DNA Binding Protein-43 (TDP-43) Associates with Stress Granules: Analysis of Cultured Cells and Pathological Brain Tissue (2010, background): “Some of the associated proteins are heat shock proteins and chaperones that might reflect the cellular response to limit protein aggregation [43].”
Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins. (2011, background): “Mutation, aging, and environmental stresses decrease proteasome activity and cause an imbalance of proteostasis, resulting in the production of misfolded proteins and the accumulation of ubiquitinated proteins (Ub proteins) and aggregates (Balch et al., 2008; Morimoto, 2008).”
The plant heat stress transcription factor (Hsf) family: structure, function and evolution. (2012, background): “Model of the human Hsf1 activity cycle (according to Akerfelt et al. [31]; modified).”
Direct Observation of the Interconversion of Normal and Toxic Forms of α-Synuclein (2012, background): “These findings highlight the key role that molecular chaperones and the cellular protein degradation machinery must play continually in preventing damage caused by such oligomers and hence the onset of disease (Balch et al., 2008; Morimoto, 2008).”
Cellular strategies for controlling protein aggregation (2010, background): “Conditions that result in aggregation The quality-control system can adapt to the severity of protein damage through the induction of stress responses, which adjust the cellular levels of chaperones and protease”
The Response to Heat Shock and Oxidative Stress in Saccharomyces cerevisiae (2012, background): “The yeast “chaperome”:With the advent of whole genome sequencing, the chaperone complement of organisms can now be determined and defined as the chaperome (Morimoto 2008).”
CARGO RECOGNITION FAILURE IS RESPONSIBLE FOR INEFFICIENT AUTOPHAGY IN HUNTINGTON’S DISEASE (2010, background): “Malfunction of the systems that contribute to cellular quality control—chaperones and proteolytic systems—leads to the accumulation of abnormal and damaged components inside cells, with subsequent functional decline and loss of cellular viabilit”
Cellular Stress Responses, The Hormesis Paradigm, and Vitagenes: Novel Targets for Therapeutic Intervention in Neurodegenerative Disorders (2010, positive): “More in general, protein quality control, which is a critical feature of intracellular homeostasis (100), is maintained by a highly complex network of molecular interactions that balances protein biosynthesis, folding, translocation, assembly = disassembly, and clearance (98, 312).”
HSF1 drives a transcriptional program distinct from heat shock to support highly malignant human cancers. (2012, positive): “Consistent with this, recent work indicates that HSF1 helps cells accommodate the complex pathophysiological derangements in protein homeostasis that underlie many human diseases, especially those associated with aging (Morimoto, 2008).”
Molecular chaperones in protein folding and proteostasis (2011, background): “Indeed, studies in model organisms indicate that ageing is linked to a gradual decline in cellular proteostasis capacit”
Amyloid-like aggregates sequester numerous metastable proteins with essential cellular functions. (2011, background): “This fundamental process is aided by a complex cellular machinery of molecular chaperones, which act to prevent misfolding and aggregation (Frydman, 2001; Hartl and Hayer-Hartl, 2002; Morimoto, 2008).”