Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging

Abstract

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.Protein homeostasis is the cellular process that governs the "life of proteins." More than protein quality control alone, protein homeostasis encompasses RNA metabolism and processing, protein synthesis, folding, translocation, assembly/disassembly, and clearance (Balch et al. 2008). These processes and their roles in protein homeostasis can be viewed as a systems network in which each process, or hub, is organized as mininetworks interconnected to other hubs. An implicit assumption of protein homeostasis is that each hub should be dynamic, and therefore have sufficient "buffering" capacity to respond to various imbalances in network components and flux of misfolded species and damaged proteins. Tissue-specific differences in expression of components of the homeostasis network such as chaperones and components of the proteasome, autophagy, or transport machinery could be a basis for the sensitivity of neuronal cells during aging and disease.Two prominent modulators of protein homeostasis are molecular chaperones and stress-inducible responses. Chaperones are abundantly expressed in multiple compartments of the cell and are thought to comprise a significant fraction of the cellular machinery (Bukau et al. 2006;Ron and Walter 2007). Only limited information is available on the concentration of chaperones in a eukaryotic cell and the fraction that is functionally engaged with substrates or freely available in reserve. Nevertheless, this has led to a commonly held expectation that within the cell, chaperones have excess folding capacity and can exist in a free state to buffer unexpected folding requirements. This would require the cell to maintain a stockpile of chaperones for protein folding emergencies. A counter view is that the cell has little excess chaperone capacity, and that the concentration of chaperones is titrat...

Aneuploidy shortens replicative lifespan in Saccharomyces cerevisiae

“…Strains disomic for larger chromosomes have been shown to overexpress a correspondingly greater number of proteins (Dephoure et al ., 2014), which would therefore be expected to cause greater disruption to proteostasis. Disrupted protein homeostasis is thought to be a general process that contributes to aging in yeast and metazoans (Morimoto, 2008). In addition to their lifespan deficit, the disrupted protein trafficking phenotype observed in the chr5 disome strain is consistent with disrupted proteostasis.…”

Firefly luciferase mutants as sensors of proteome stress

“…During aging, there is a progressive decline in the efficiency of protein quality control mechanisms (Gidalevitz et al, 2006;Morimoto, 2008) (Figure 12). This deficit in the proteostasis capacity predisposes individuals to many late-age onset diseases including neurodegenerative diseases such as AD, PD and HD and other maladies like diabetes type II, myopathies etc.…”

Specific protein homeostatic functions of small heat‐shock proteins increase lifespan

“…The imbalance in overall protein homeostasis is a crucial factor in the development of heritable age‐related neurodegenerative diseases and during normal aging (Dobson, 2003; Vacher et al ., 2005; Zhang et al ., 2005; Arslan et al ., 2006; Haass & Selkoe, 2007; Morimoto, 2008). Achieving and maintaining the correct three‐dimensional protein structure is a continuous struggle within cells.…”

“…By their ability to bind non‐native polypeptides, they maintain their substrates in a state competent for subsequent folding or, when folding is not successful, for degradation by the ubiquitin–proteasome system (Urushitani et al ., 2004) or through autophagy (Carra et al ., 2008). Hereby chaperones can prevent toxic protein aggregation, and as such, they have been implicated as protectors against age‐related protein folding diseases (Rujano & Kampinga, 2008) and as supporters of healthy aging (Hsu et al ., 2003; Morrow & Tanguay, 2003; Walker & Lithgow, 2003; Morley & Morimoto, 2004; Morimoto, 2008). Indeed, activation of all stress‐inducible HSPs, either by overexpression of the heat‐shock factor‐1 (HSF‐1) (Morley & Morimoto, 2004; Morimoto, 2008) or via caloric restriction and the accompanying insulin signaling (Hsu et al ., 2003), was shown to delay the onset of protein folding diseases and to induce longevity in otherwise healthy animals.…”