Proteostasis

Proteostasis refers to controlling the concentration, three-dimensional structure, binding interactions and subcellular or extracellular location of individual proteins making up the proteome by adapting the innate biology of the cell, generally through transcriptional and translational changes. Proteostasis thus alters specific cellular functions and enables tissues to change their physiology for successful organismal development and aging in the face of constant intrinsic and extrinsic challenges to prevent pathology. Proteostasis is influenced by the chemistry of protein folding and aggregation and by numerous regulated networks of interacting and competing biological pathways including chaperones, folding enzymes, disaggregase activity(ies), degradation activities, etc) that are regulated by aging and other stress signaling pathways, the unfolded protein response signaling pathway, as well as the heat shock response signaling pathway. Restoring proteostasis can correct proteostatic deficiencies that lead to a spectrum of human diseases, some that present at birth, but most upon aging-explained by the emerging hypothesis that aging signaling pathways directly control proteostasis.

When Proteostasis is compromised, it can result in loss-of-function diseases including the lysosomal storage diseases or cystic fibrosis or gain-of-function degenerative diseases associated with protein aggregation such as Huntington's disease, Alzheimer's disease as well as other amyloid diseases. Proteostasis can be rebalanced to ameliorate disease either genetically or by using small molecules or biological macromolecules that rebalance the proteostasis network, so called Proteostasis Regulators. This has been demonstrated in patient derived cell lines and in animal models of human disease providing optimism that Proteostasis Regulators could someday become a new class of drugs.

Reference
(William E. Balch, Richard I. Morimoto, Andrew Dillin and Jeffery W. Kelly Science, 2008, 319, 916-919 and references cited therein)

"Other papers that refer to Proteostasis include"

(R. I. Morimoto (2008) Genes & Dev. 22, 1427-1438)

(B. Caughey and G. S. Baron (2008) PNAS 105, 7113-7114)

(Xing G, Qualls C, Huicho L, River-Ch M, Stobdan T, Slessarev M, Prisman E, Ito S, Wu H, Norboo A, Dolma D, Kunzang M, Norboo T, Gamboa JL, Claydon VE, Fisher J, Zenebe G, Gebremedhin A, Hainsworth R, Verma A, Appenzeller O PLoS ONE. 2008 Jun 4;3(6):e2342)

(A. Wuster and M.M. Babu Trends in Biotechnology, 2008, 26, 252-258)

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