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.

Figure 1.

Chaperone networks and the regulation of protein conformation. The unfolded protein transitions to the intermediate and native state assisted by molecular chaperones. The “holding” activity of chaperones is represented by formation of transient and stable intermediates that continue on-pathway to the native state upon interaction with an ATP-dependent chaperone machine such as Hsp70 (together with ATP and the cochaperones Bag1, Hip, and Hdj1). Unfolded proteins and intermediates can form aggregates that can be rescued by the Hsp104 class of chaperones. Likewise, intermediates can form aggregates, become degraded, or fold to the native state assisted by chaperones.

Figure 2.

Cell stress response. The expression of HS genes including chaperones and components of the clearance machinery is induced in response to three classes of physiological and environmental stress conditions including environmental stress, pathophysiological stress, and protein conformational disease, and by a fourth class of cell growth and development. Indicated below each major class are representative conditions known to involve the expression of heat-shock proteins and chaperones.

Figure 3.

Interplay between protein quality control (transition of unfolded to intermediates to native states) and clearance mechanisms in protein conformation disease. Chaperones have a critical role to suppress the appearance of misfolded species and to enhance protein folding. The imbalance of misfolded species is associated in human disease with premature clearance of CFTR as occurs in cystic fibrosis, to prevent improper trafficking of α-1-anti-trypsin as occurs in emphysema, and to prevent proteins from adopting toxic folds as in amyloidoses including huntingtin in Huntington’s disease, α-synuclein and parkin in Parkinson’s disease, mutant SOD1 in familial ALS, and Aβ in Alzheimer’s disease.

Figure 4.

PolyQ length and age-dependent aggregation toxicity in C. elegans. Animals expressing different lengths of polyQ-YFP (Q0, Q24, Q35, Q40, and Q82) exhibit a length-dependent aggregation phenotype in day 4 young adult animals. Intermediate lengths of polyQ (i.e., Q35) show an age-dependent aggregation phenotype of soluble protein at day 4 and increasing numbers of aggregates in day 7 and day 10 of adulthood. The graph shows that there is a corresponding age-dependent increase in cellular toxicity (loss of motility) with polyQ expansion. Figure adapted from Morley et al. (2002).

Figure 5.

Roles of the ILS pathway and HSF1 in aggregation toxicity and longevity. Both HSF1 and DAF-16 are essential components and function in concert to promote longevity and to maintain protein homeostasis. Reduction of the ILS signal (depicted by the X) leads to the activation of DAF-16 and enhancement of life span.