The biology of proteostasis in aging and disease

Abstract

Loss of protein homeostasis (proteostasis) is a common feature of aging and disease that is characterized by the appearance of nonnative protein aggregates in various tissues. Protein aggregation is routinely suppressed by the proteostasis network (PN), a collection of macromolecular machines that operate in diverse ways to maintain proteome integrity across subcellular compartments and between tissues to ensure a healthy life span. Here, we review the composition, function, and organizational properties of the PN in the context of individual cells and entire organisms and discuss the mechanisms by which disruption of the PN, and related stress response pathways, contributes to the initiation and progression of disease. We explore emerging evidence that disease susceptibility arises from early changes in the composition and activity of the PN and propose that a more complete understanding of the temporal and spatial properties of the PN will enhance our ability to develop effective treatments for protein conformational diseases.

Keywords: aggregation; chaperones; neurodegenerative disease; protein folding; protein misfolding; stress response.

Figure 1

Overview of the proteostasis network (PN). The human PN must ensure proteome stability across cellular compartments (not drawn to scale). Molecular chaperones of the HSP70 (blue spheres), HSP40/DNAJ (red spheres), and HSP90 (green spheres) families are found in all major cellular compartments and cooperate with cochaperones (gray spheres) to promote folding of nascent chains, assembly of protein complexes, refolding of misfolded clients (serrated red spheres), or degradation of terminally misfolded substrates by the proteasome. Small heat shock protein (sHSP) homo-oligomers bind misfolded proteins and maintain them in a folding-competent state for the HSP70 machinery. If refolding is unsuccessful, cooperation with the nucleotide exchange factor Bcl2-associated athanogene 1 (BAG1) and the E3 ubiquitin ligase C terminus of HSC70-interacting protein (CHIP) can direct substrates to the proteasome. The HSP60 family of chaperones is crucial for mitochondrial proteostasis (in conjunction with the “lid” cochaperone HSP10) and for folding of cytoskeletal components via the TCP-1 ring complex (TRiC). Certain chaperones and cochaperones perform specialized or compartment-specific functions (orange spheres). For example, in the endoplasmic reticulum (ER), protein disulfide isomerase (PDI) and ER oxidoreductin 1 (ERO1) cooperate to promote disulfide bond formation, while calnexin (CANX) and calreticulin (CALR) perform calcium-dependent folding of substrates. Upon protein misfolding, specific stress response pathways such as the heat shock response (HSR) and unfolded protein responses of the ER (UPR^ER) and mitochondria (UPR^mito) can boost chaperone levels. Occasionally, misfolded proteins can form aggregates that can be deleterious to cells. HSP110 cooperates with HSP70/HSP40 to act as a disaggregase. Alternatively, large aggregates can be degraded by the lysosome through autophagy. A modification of this pathway (mitophagy) can also be used to remove old or damaged mitochondria. Gray arrows indicate pathways that should occur only at low levels in healthy cells. Abbreviations: DUB, deubiquitinating enzyme; ERAD, ER-associated degradation; mRAC, mammalian ribosome-associated complex; NAC, nascent polypeptide chain–associated complex; Ub, ubiquitin.

Figure 2

Disruption of the proteostasis network (PN) in aging and disease. Numerous mechanisms contribute to proteostasis collapse in neurodegenerative disease and aging. Principal among these are reduced levels of soluble chaperones and disruption of protein degradation pathways. The action of HSP70 (blue spheres), HSP40/DNAJ (red spheres), and cochaperones (gray spheres) ensures that newly synthesized proteins fold properly (green spheres). Upon protein misfolding (serrated green spheres), molecular chaperones can either refold substrates to a functional conformation or direct substrates to the proteasome for degradation in the cytosol or nucleus. The presence of aggregation-prone proteins (serrated red spheres) sequesters chaperones and impairs the heat shock response (HSR). Reduced chaperone levels impair clathrin-mediated endocytosis (CME) (actually, HSC70 and auxilin reside within the clathrin cage) and inefficient degradation of ubiquitin (Ub)-conjugated substrates. As chaperone levels become compromised, the likelihood of protein misfolding and aggregation is exacerbated, driving neuronal dysfunction and disease. Protein aggregates can also spread between cells, thereby propagating proteostasis collapse. Red arrows denote pathways dysregulated in aging and/or neurodegenerative disease. Abbreviations: HSF1, heat shock factor 1; HSE, heat shock element; HSP, heat shock protein; mRAC, mammalian ribosome-associated complex; NAC, nascent polypeptide chain–associated complex.

Figure 3

Proposed models for the relationship between proteostasis collapse, aging, and disease. Proteostasis collapse is associated with aging and disease in multiple tissues. High proteostasis capacity early in life maintains proteome integrity (green spheres) and minimizes the risk of disease (unshaded areas). The conventional model of aging proposes that proteostasis capacity declines progressively with age, leading to increased incidence of protein misfolding (red spheres). Once proteostasis capacity falls below a certain threshold, proteome integrity is widely compromised and leads to disease (shaded areas). An alternate model emerging from studies in Caenorhabditis elegans is that proteostasis capacity collapses early in adulthood and may be part of a programmed event, thereby resulting in a longer window of disease susceptibility. It is possible that tissues (colored lines) exhibit the same or differential patterns of proteostasis collapse during life, which, coupled with specific mutations, result in a specific pattern of disease presentation and progression.