Chaperone networks: tipping the balance in protein folding diseases

Abstract

Adult-onset neurodegeneration and other protein conformational diseases are associated with the appearance, persistence, and accumulation of misfolded and aggregation-prone proteins. To protect the proteome from long-term damage, the cell expresses a highly integrated protein homeostasis (proteostasis) machinery to ensure that proteins are properly expressed, folded, and cleared, and to recognize damaged proteins. Molecular chaperones have a central role in proteostasis as they have been shown to be essential to prevent the accumulation of alternate folded proteotoxic states as occurs in protein conformation diseases exemplified by neurodegeneration. Studies using invertebrate models expressing proteins associated with Huntington's disease, Alzheimer's disease, ALS, and Parkinson's disease have provided insights into the genetic networks and stress signaling pathways that regulate the proteostasis machinery to prevent cellular dysfunction, tissue pathology, and organismal failure. These events appear to be further amplified by aging and provide evidence that age-related failures in proteostasis may be a common element in many diseases.

Figure 1. Multiple chaperone and co-chaperone families assist in protein folding

Chaperones guide the protein fold starting with the initial steps of protein synthesis. As a nascent chain exits the ribosome channel, a series of chaperones bind the extended polypeptide, interacting with the protein throughout its maturation into the native folded state. Chaperone assisted folding involves the core chaperone families, Hsp70, Hsp90 and TRiC. Specific co-chaperones modulate the folding activities of core chaperones depending on substrate and the step in the folding pathway. Additionally, chaperones protect the native fold during denaturing stresses that unfold or damage cellular proteins. Hsp100s and small Hsps prevent protein aggregation and work with chaperones to refold denatured cellular proteins. Specific co-chaperones recognize substrates and cooperate with core chaperones, determining the fate of the damaged protein. The chaperone quality control system directs the protein either for refolding or degradation by the proteasome.

Figure 2. C. elegans models of protein misfolding

Length-dependent aggregation of polyQ-YFP fusion proteins expressed in body wall muscle cells (A) or neurons (B). Epifluoresence micrographs of 3- to 4-day-old animals expressing different lengths of polyQ-YFP. Scale bar = 0.1 mm (A), or scale bar = 50 um (B). Influence of aging on polyQ aggregation (C) and toxicity (D). (C) Number of aggregates in Q82 (○), Q40 (•), Q35 (□), Q33 (■), Q29 (△), and Q0 (▲) that accumulate during aging. Data are mean +/- SEM. Each data point represents at least five animals. (D) Motility index as a function of age for the same cohorts of animals described in C. Data are mean +/- SD as a percentage of age-matched Q0 animals.

Figure 3. Integration of stress responses and aging in C. elegans

Stress responses are mediated through at least three transcription factors, HSF-1, DAF-16 and SKN-1. Ability of the animals to respond to various stresses decreases dramatically with age. Dietary restriction (DR), reduced insulin-like signaling (ILS) and various stresses activate cellular pathways leading to transcription of specific chaperone networks and other proteostasis machinery. Integration of these signals leads to coordination of the proper response that facilitates stress resistance and longevity in addition to suppression of proteotoxicity.

Figure 4. Proteostasis networks maintain functionality throughout lifespan

Under normal conditions, the proteostasis machinery, which includes molecular chaperones, maintains a properly folded proteome in young animals. However, chronic expression of aggregation prone proteins or accumulation of damaged proteins during aging can lead to depletion of chaperones and components of the proteostasis machinery resulting in protein misfolding. Reduction of insulin signaling and dietary restriction activate transcriptional networks leading to expression of key chaperone components. These components facilitate chaperone mediated refolding and clearance of damaged proteins, rebalancing cellular protein homeostasis. As a consequence, functionality is restored, increasing the healthspan of the organism.