Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University, Evanston, IL 60208-3500, USA.
Curr Opin Struct Biol. 2010 Feb;20(1):23-32. doi: 10.1016/j.sbi.2009.11.001. Epub 2010 Jan 5.
The inherently error-prone nature of protein biosynthesis and turnover leads to a constant flux of destabilized proteins. Genetic mutations in conformational disease-associated proteins, as well as exposure to acute and chronic proteotoxic stresses, further increase the load of misfolded protein on the proteostasis network. During aging, this leads to enhanced instability of the proteome, failure to buffer destabilizing genetic mutations or polymorphisms, and cellular decline. The combination of cell-type-specific differences in the buffering capacity of the proteostasis network and destabilizing polymorphisms in the genetic background may account for some of the cell-type specificity observed in disease, even when the predominant disease-associated protein is widely expressed.
蛋白质生物合成和周转的固有易错性质导致不稳定蛋白质不断流动。构象疾病相关蛋白的遗传突变，以及急性和慢性蛋白毒性应激的暴露，进一步增加了错误折叠蛋白对蛋白稳态网络的负担。随着年龄的增长，这会导致蛋白质组的稳定性增强，无法缓冲不稳定的遗传突变或多态性，从而导致细胞衰退。蛋白稳态网络的缓冲能力的细胞类型特异性差异以及遗传背景中的不稳定多态性的组合，可能解释了即使在主要的疾病相关蛋白广泛表达的情况下，疾病中观察到的一些细胞类型特异性现象。
