Protein homeostasis and aging in neurodegeneration

Abstract

Genetic and environmental factors responsible for numerous neurodegenerative diseases vary between disorders, yet age remains a universal risk factor. Age-associated decline in protein homeostasis, or proteostasis, enables disease-linked proteins to adopt aberrant tertiary structures, accumulate as higher-ordered aggregates, and cause a myriad of cellular dysfunctions and neuronal death. However, recent findings suggest that the assembly of disease proteins into tightly ordered aggregates can significantly delay proteotoxic onset. Furthermore, manipulation of metabolic pathways through key signaling components extends lifespan, bolsters proteostasis networks, and delays the onset of proteotoxicity. Thus, understanding the relationship between proteostasis and aging has provided important insights into neurodegeneration.

Figure 1.

Proteostasis landscape deteriorates with time. Integrated components of the protein homeostasis network are arbitrarily represented as a global landscape. General activity for transcription, translation, folding, trafficking, processing, assembly/disassembly, localization, and degradation are depicted as nodes in which node amplitude signifies strength of homeostatic activity. Nodes are designated with the color indicated in the legend below and assigned an arbitrary value for activity. Proteomic breakdown resultant from age can be attributed to a general deterioration in each proteostasis hub.

Figure 2.

Environment influences neurodegeneration through age modifiers and proteostasis networks. Environmental cues such as food availability or extrinsic stress alter age-modifying, signaling pathways such as insulin/IGF-1, target of rapamycin (TOR), sirtuins, heat shock factor (HSF), and hypoxia-inducible factor (HIF-1). Elaborate interplay between the different signaling pathways modulates proteostasis and impacts onset and progression of numerous neurodegenerative diseases.

Figure 3.

Aging modifiers intervene in the life of disease proteins. The model depicts synthesis, folding, processing, degradation, and aggregation of an arbitrary disease-linked protein. Age modifiers including TOR, sirtuins, and insulin/IGF-1 act at multiple points within the protein aggregation cascade to ameliorate the accumulation of proteotoxic intermediates. The corresponding letters A–L are briefly described and referenced in Table I.