专题：Science系列
一种新药可通过清除罹患某种肌肉营养障碍的小鼠体内的突变蛋白而增强其肌肉的力量。 这种药叫做cystamine （胱胺），它也许能使人们更好地治疗那些罹患无法治愈的退行性的肌肉疾病。
在这一研究中，科研人员聚焦于眼咽型肌肉营养障碍（OPMD），该疾病主要影响面部的肌肉，使得面肌和眼睑下垂。 该病的症状通常要到45岁或50多岁的时候才开始出现，但其症状也可提前出现。当人们用高倍显微镜检查OPMD患者的肌肉组织时，他们可以看见在肌肉细胞内有块状的蛋白质，它们是由一个缺陷基因所产生的多余的化学物质。
如今，Janet Davies及其同僚证明，一种叫做谷氨酰胺转胺酶的活性在OPMD的小鼠模型中比正常状态要高。研究人员研究了从小鼠到人的肌肉细胞，并证明，引起OPMD的突变蛋白的毒性和积块在谷氨酰胺转胺酶浓度增高时会有所增加。同样地，如果该酶的活性水平被胱胺（它是一种已知的抑制剂）抑制时，突变蛋白的浓度和积块也会降低。接受了胱胺治疗的小鼠的肌肉会变得较强壮，而且其蛋白积块比未经治疗的小鼠要少。这些结果提示，该药可能会通过减少突变蛋白的积块及可能保护细胞免于死亡而给OPMD的患者带来裨益。人们还需要开展进一步的研究来测试胱胺是否对人的疾病也有效。
推荐原文出处：
Sci Transl Med DOI: 10.1126/scitranslmed.3000723
Cystamine Suppresses Polyalanine Toxicity in a Mouse Model of Oculopharyngeal Muscular Dystrophy
Janet E. Davies*, Claudia Rose*, Sovan Sarkar and David C. Rubinsztein?
Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 0XY, UK.
Oculopharyngeal muscular dystrophy (OPMD) is caused by a trinucleotide repeat expansion mutation in the coding region of the gene encoding PABPN1 (polyadenylate-binding protein nuclear 1). Mutant PABPN1 with a polyalanine tract expansion forms aggregates within the nuclei of skeletal muscle fibers. There is currently no effective treatment. We have developed cell and mouse models of OPMD and have identified the aggregation of mutant PABPN1 and apoptosis as therapeutic targets. Here, we show that transglutaminase activity is increased in muscle from OPMD model mice. Elevated transglutaminase 2 expression enhances, whereas TG2 knockdown suppresses, the toxicity and aggregation of mutant PABPN1 in cells. Cystamine protects against the toxicity of mutant PABPN1 and exerts its effect via the inhibition of transglutaminase 2, as cystamine treatment is unable to further reduce the protective effect of transglutaminase 2 knockdown on mutant PABPN1 toxicity in cells. Cystamine also reduces the aggregation and toxicity of mutant PABPN1 in human cells. In a mouse model of OPMD, cystamine treatment reduced the elevated transglutaminase activity, attenuated muscle weakness, reduced aggregate load, and decreased apoptotic markers in muscle. Therefore, inhibitors of transglutaminase 2 should be considered as possible therapeutics for OPMD.
