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In addition, applications in the area of biomarkers may be available in the near future through the identification of specific patterns of stressgene expression that may reflect the disease state of the brain.It is also important to highlight the fact that only a few studies have directly addressed the impact of PERK on neurodegeneration, Glipizide Because most of the manipulations have been performed at the level of eIF phosphorylation or its downstream responses, which are not exclusive to the ER stressUPR pathway.The most recognized function of the UPR in physiology is the support of secretorycell function; however, this concept has not been directly addressed in the ner vous system.It remains to be determined whether myelin synthesis per se constitutes a physiological source of ER stress.With this in mind, it is an open question as to whether the UPR can modulate the differentiation of these cell types, as observed in specialized secretory cells.Neuropeptideproducing neurons are also an attractive population of brain cells that need to be investigated in detail in the context of the UPR. Another area of research that is fully open is brain inf lammation.The UPR has a demonstrated impact on Flurbiprofen various immune cells, in which it regulates the secretion of proinflammatory cytokines and innate immunity signals.Because most pathologies of the CNS involve brain inflammation, the actual impact of the UPR on microglial and astrocyte function should be studied in depth.The advances in thefield in the past years are revolut ionar y, owing to the generation of mice in which essential UPR components have been genetically modified and to the recent discovery of small molecules that target essential UPR compo nents.Science. All rights reserved The user has requested enhancement of the downloaded file.View publication stats View publication stats Under optimal conditions this is accomplished by protein homeostasis, a highly complex network of molecular interactions that balances protein biosynthesis, folding, translocation, assemblydisassembly, and clearance.This review will examine the consequences of an imbalance in homeostasis on the flux of misfolded proteins that, if unattended, can result in severe molecular damage to the cell.Adaptation and survival requires the ability to sense damaged proteins and to coordinate the activities of protective stress response pathways and chaperone networks.Yet, despite the abundance and apparent capacity of chaperones and other components of homeostasis to restore folding equilibrium, the cell appears poorly adapted for chronic proteotoxic stress when conformationally challenged aggregationprone proteins are expressed in cancer, metabolic disease, and neurodegenerative disease.The decline in biosynthetic and repair activities that compromises the integrity of the proteome is influenced strongly by genes that control aging, thus linking stress and protein homeostasis with the health and life span of the organism.These processes and their roles in protein homeostasis can be viewed as a systems network in which each process, or hub, is organized as mininetworks interconnected to other hubs.Chaperones are abundantly expressed in multiple compartments of the cell and are thought to comprise a significant fraction of the cellular machinery. Only limited information is available on the concentration of chaperones in a eukaryotic cell and the fraction that is functionally engaged with substrates or freely available in reserve.

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