期刊
ANNUAL REVIEW OF BIOCHEMISTRY
卷 78, 期 -, 页码 959-991出版社
ANNUAL REVIEWS
DOI: 10.1146/annurev.biochem.052308.114844
关键词
aging; amyloid; chaperones; heat shock response; protein folding and misfolding; unfolded protein response
资金
- NIH [GM033301, GM042336, HL079442, AG031097, DK05187, DK046335, AG018917, DK07529, GM038109, GM081192, AG026647, NS047331]
- Lita Annenberg Hazen Foundation
- Bruce Ford and Anne Smith Bundy Foundation
- Skaggs Institute for Chemical Biology
- McKnight Foundation for Neuroscience
- HHMI
- Cystic Fibrosis Foundation
- Genomics Institute of the Novartis Foundation
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL079442] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [T32DK007529, R37DK046335, R01DK046335, R29DK046335] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM042336, R01GM038109, R37GM038109, R01GM033301] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS047331] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG026647, R01AG018917, P01AG031097] Funding Source: NIH RePORTER
Many diseases appear to be caused by the misregulation of protein maintenance. Such diseases of protein homeostasis, or proteostasis, include loss-of-function diseases (cystic fibrosis) and gain-of-toxic-function diseases (Alzheimer's, Parkinson's, and Huntington's disease). Proteostasis is maintained by the proteostasis network, which comprises pathways that control protein synthesis, folding, trafficking, aggregation, disaggregation, and degradation. The decreased ability of the proteostasis network to cope with inherited misfolding-prone proteins, aging, and/or metabolic/environmental stress appears to trigger or exacerbate proteostasis diseases. Herein, we review recent evidence supporting the principle that proteostasis is influenced both by an adjustable proteostasis network capacity and protein folding energetics, which together determine the balance between folding efficiency, misfolding, protein degradation, and aggregation. We review how small molecules can enhance proteostasis by binding to and stabilizing specific proteins (pharmacologic chaperones) or by increasing the proteostasis network capacity (proteostasis regulators). We propose that such therapeutic strategies, including combination therapies, represent a new approach for treating a range of diverse human maladies.
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