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修复蛋白被激活帮助肌肉萎缩症患者生成肌肉细胞

来源:生物谷 2014-08-23 22:07

2014年8月23日 讯 /生物谷BIOON/ --当肌肉细胞膜遭到破坏,修复蛋白质dysferlin就会被激活并且重新帮助生成肌肉细胞膜。如果这种修复蛋白质由于基因突变被改变,那么人体自身的“质量控制”系统(即蛋白酶体)就认为该蛋白质是缺陷的继而消除它。如果没有dysferlin蛋白,那么受伤的肌肉细胞膜就不能被修复,从而导致骨骼肌细胞逐渐损失最终致使肌肉萎缩。看来,人体自身的“质量控制体系"会中和突变蛋白质dysferlin,即使这种突变体并不会损害它的修复功能。

修复蛋白质重新被激活。Michael Sinnreich教授领导的研究小组曾证实,蛋白酶体抑制剂可以激活培养的肌肉细胞中发生突变的dysferlin蛋白质,这种肌肉细胞取自肌肉萎缩症患者体内。大量的蛋白酶体抑制剂使变异的修复蛋白能恢复其功能并且修复受损的肌肉细胞膜。该小组已经将调查结果转化为临床应用。在理论水平的研究中,该结论中蛋白酶体抑制剂修复肌肉萎缩症患者骨骼肌中失踪的dysferlin蛋白质。体内含有dysferlin突变体的三个病人获得了体内所需要剂量的蛋白酶体抑制剂。几天后,病人的肌肉组织中产生了失踪dysferlin蛋白质,该蛋白质可能在临床上有重要作用。

该项研究的研究主管Michael Sinnreich说:“新的发现为未来的长期临床试验奠定了基础,这些发现可能对治疗肌肉萎缩症以及其它以前无法治愈的遗传疾病非常重要。”(生物谷Bioon.com)

 

Proteasome inhibitors increase missense mutated dysferlin in patients with muscular dystrophy

Bilal A. Azakir1, Beat Erne1, Sabrina Di Fulvio1, Guido Stirnimann2 and Michael Sinnreich1,*

 

No treatment is available for patients affected by the recessively inherited, progressive muscular dystrophies caused by a deficiency in the muscle membrane repair protein dysferlin. A marked reduction in dysferlin in patients harboring missense mutations in at least one of the two pathogenic DYSF alleles encoding dysferlin implies that dysferlin is degraded by the cell’s quality control machinery. In vitro evidence suggests that missense mutated dysferlin might be functional if salvaged from degradation by the proteasome. We treated three patients with muscular dystrophy due to a homozygous Arg555Trp mutation in dysferlin with the proteasome inhibitor bortezomib and monitored dysferlin expression in monocytes and in skeletal muscle by repeated percutaneous muscle biopsy. Expression of missense mutated dysferlin in the skeletal muscle and monocytes of the three patients increased markedly, and dysferlin was correctly localized to the sarcolemma of muscle fibers on histological sections. Salvaged missense mutated dysferlin was functional in a membrane resealing assay in patient-derived muscle cells treated with three different proteasome inhibitors. We conclude that interference with the proteasomal system increases expression of missense mutated dysferlin, suggesting that this therapeutic strategy may benefit patients with dysferlinopathies and possibly other genetic diseases.

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