Fox Chase癌症研究中心的研究人员称，或许可以通过增强细胞修复自身突变蛋白的能力，最终达到治疗遗传性疾病的效果。他们发现，细胞在蛋白酶抑制剂(proteosome inhibitors)的作用下，可产生大量的分子伴侣Hsp70，这种伴侣蛋白能够协助氨基酸链折叠成为正确的构象。这项最新发现发表在PLoS Genetics杂志上。
据研究人员Warren Kruger介绍，Hsp70能够将发生错误折叠的突变蛋白分开——类似于解开扭成一团的橡皮筋，并最终使错误折叠的蛋白恢复到原来的正确构象。如果这种机制也同样适用于人类，那么对科学家研究因蛋白质错误折叠引起的某些遗传病提供新的研究方向。
错义突变(missense mutation)往往导致一些遗传病的发生。由于蛋白质的形状取决于特定氨基酸的排列，因此即使基因发生了一个很小的突变，也会导致蛋白质产物出现畸形。在该课题中，研究人员对三种因错义突变导致的遗传病进行研究，其中两种是遗传性代谢疾病，另外一种是遗传性癌症综合症。
研究人员发现，通过诱导，使细胞中伴侣蛋白Hsp70的水平升高，可以使突变蛋白的恢复到正常功能。而且Hsp70含量越丰富，修复成功的可能性越高。
在临床上，目前已开发出几种可应用于增加人类Hsp70的药物，用其中一种药物bortezomib处理酵母和哺乳动物细胞后发现，细胞中Hsp70水平上升。Bortezomib是一种蛋白酶体抑制剂，能够降低细胞中某些蛋白质的功能，目前用于多发性骨髓细胞瘤的治疗。
但目前研究人员需要解决的问题是，如果使细胞中的Hsp70长期处于较高水平，那么对细胞自身安全性将会产生何种影响。（生物谷Bioon.com）
生物谷推荐原始出处：
PLoS Genet 6(1): e1000807. doi:10.1371/journal.pgen.1000807
Activation of Mutant Enzyme Function In Vivo by Proteasome Inhibitors and Treatments that Induce Hsp70
Laishram R. Singh1, Sapna Gupta1, Nicholaas H. Honig1, Jan P. Kraus2, Warren D. Kruger1*
1 Cancer Genetics and Signaling Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America, 2 Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, United States of America
Missense mutant proteins, such as those produced in individuals with genetic diseases, are often misfolded and subject to processing by intracellular quality control systems. Previously, we have shown using a yeast system that enzymatic function could be restored to I278T cystathionine β-synthase (CBS), a cause of homocystinuria, by treatments that affect the intracellular chaperone environment. Here, we extend these studies and show that it is possible to restore significant levels of enzyme activity to 17 of 18 (94%) disease causing missense mutations in human cystathionine β-synthase (CBS) expressed in Saccharomyces cerevisiae by exposure to ethanol, proteasome inhibitors, or deletion of the Hsp26 small heat shock protein. All three of these treatments induce Hsp70, which is necessary but not sufficient for rescue. In addition to CBS, these same treatments can rescue disease-causing mutations in human p53 and the methylene tetrahydrofolate reductase gene. These findings do not appear restricted to S. cerevisiae, as proteasome inhibitors can restore significant CBS enzymatic activity to CBS alleles expressed in fibroblasts derived from homocystinuric patients and in a mouse model for homocystinuria that expresses human I278T CBS. These findings suggest that proteasome inhibitors and other Hsp70 inducing agents may be useful in the treatment of a variety of genetic diseases caused by missense mutations.
