A Systems Approach to Cell Stress and Proteostasis Networks
（細胞ストレスとプロテオスタシスネットワークへのシステムアプローチ）

The proteostasis network (PN), comprised of cell stress signaling pathways, molecular chaperones and clearance machineries, have a central role for cellular health, for organismal longevity, and to prevent protein aggregation. 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 reponses. During aging, for example, the expression patterns of chaperone genes reveal distinct network signatures of activation and repression. The subsets of chaperones that are activated or repressed 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 A beta 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 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.