Fox Chase癌癥研究中心的研究人員稱，或許可以通過增強(qiáng)細(xì)胞修復(fù)自身突變蛋白的能力,，最終達(dá)到治療遺傳性疾病的效果,。他們發(fā)現(xiàn)，細(xì)胞在蛋白酶抑制劑(proteosome inhibitors)的作用下,，可產(chǎn)生大量的分子伴侶Hsp70，這種伴侶蛋白能夠協(xié)助氨基酸鏈折疊成為正確的構(gòu)象,。這項(xiàng)最新發(fā)現(xiàn)發(fā)表在PLoS Genetics雜志上,。
據(jù)研究人員Warren Kruger介紹,，Hsp70能夠?qū)l(fā)生錯(cuò)誤折疊的突變蛋白分開——類似于解開扭成一團(tuán)的橡皮筋，并最終使錯(cuò)誤折疊的蛋白恢復(fù)到原來的正確構(gòu)象,。如果這種機(jī)制也同樣適用于人類,，那么對(duì)科學(xué)家研究因蛋白質(zhì)錯(cuò)誤折疊引起的某些遺傳病提供新的研究方向。
錯(cuò)義突變(missense mutation)往往導(dǎo)致一些遺傳病的發(fā)生,。由于蛋白質(zhì)的形狀取決于特定氨基酸的排列,，因此即使基因發(fā)生了一個(gè)很小的突變，也會(huì)導(dǎo)致蛋白質(zhì)產(chǎn)物出現(xiàn)畸形,。在該課題中,，研究人員對(duì)三種因錯(cuò)義突變導(dǎo)致的遺傳病進(jìn)行研究，其中兩種是遺傳性代謝疾病,，另外一種是遺傳性癌癥綜合癥,。
研究人員發(fā)現(xiàn)，通過誘導(dǎo),，使細(xì)胞中伴侶蛋白Hsp70的水平升高,，可以使突變蛋白的恢復(fù)到正常功能。而且Hsp70含量越豐富,，修復(fù)成功的可能性越高,。
在臨床上，目前已開發(fā)出幾種可應(yīng)用于增加人類Hsp70的藥物,，用其中一種藥物bortezomib處理酵母和哺乳動(dòng)物細(xì)胞后發(fā)現(xiàn),，細(xì)胞中Hsp70水平上升。Bortezomib是一種蛋白酶體抑制劑,，能夠降低細(xì)胞中某些蛋白質(zhì)的功能,，目前用于多發(fā)性骨髓細(xì)胞瘤的治療。
但目前研究人員需要解決的問題是,，如果使細(xì)胞中的Hsp70長(zhǎng)期處于較高水平,，那么對(duì)細(xì)胞自身安全性將會(huì)產(chǎn)生何種影響。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
