Cell Stress and Proteostasis Networks in Biology, Aging, and Disease

Abstract

The proteostasis network (PN) is comprised of cell stress signaling pathways, molecular chaperones and clearance machineries that is central to prevent protein aggregation, to maintain cellular health, and to ensure organismal longevity. Under optimal conditions, the PN minimizes the stress of misfolded and aggregation-prone proteins that arise from genetic polymorphisms, error-prone synthesis, mutations, stress, and aging. This is achieved by the properties of the heat shock response, the unfolded protein responses, and antioxidant stress responses. During aging, the expression of chaperone genes reveal network signatures of repression indicative of imminent proteostasis failure. The subsets of chaperones that are repressed or activated during aging show similar accelerated changes in brain tissue from Alzheimer's, Huntington's and Parkinson's disease patients, of which a sub-set defining a core prevent misfolding and proteotoxicity of Aβ and polyQ expressed in C. elegans. Stress and aging cause fluctuations in protein quality control that are costly and can disrupt the PN, causing proteome mismanagement and collateral damage to metastable proteins and amplification of non-native species. Transmission of the environmental stress signal involves both intracellular proteotoxicity and cell non-autonomous signaling between neurons and somatic tissues and between somatic tissues to ensure that cellular responses to stress are coordinated by transcellular chaperone signaling for organismal survival. The enhanced risk for misfolding during aging, therefore, contributes substantially to age-associated diseases including neurodegeneration, cancer, immunological disease, and metabolic disease.