Therapeutic potential of proteasome inhibition in Duchenne and Becker muscular dystrophies.
Therapeutic potential of proteasome inhibition in Duchenne and Becker muscular dystrophies.
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蛋白酶体抑制对杜兴肌营养不良症和贝克肌营养不良症的治疗潜力。
DOI：
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发表时间：
2010
影响因子：
6
通讯作者：
C. Minetti
中科院分区：
文献类型：
--
作者：
E. Gazzerro;S. Assereto;A. Bonetto;F. Sotgia;S. Scarfì;A. Pistorio;G. Bonuccelli;M. Cilli;C. Bruno;F. Zara;M. Lisanti;C. Minetti
Duchenne肌营养不良症(DMD)及其较轻微的等位基因变异Becker肌营养不良症(BMD)是由dystrophin基因突变引起的，并导致肌肉进行性恶化。蛋白酶体降解的增强是DMD/BMD营养不良过程发病机制中的关键步骤。此前，我们证明了蛋白酶体抑制剂MG-132的治疗挽救了Dstrophin和Dstrophin糖蛋白复合体在MDX小鼠的细胞膜定位，MDX小鼠是DMD的自然遗传小鼠模型。目前的工作旨在彻底确定VELCADE对营养不良症的治疗潜力，VELCADE是一种选择性阻断泛素-蛋白酶体途径的药物。VELCADE特别耐人寻味，因为它已被批准用于治疗多发性骨髓瘤。因此，它对人类的副作用已经被探索出来了。VELCADE效应通过两种独立的方法进行分析。首先，我们在MDX小鼠身上系统地给药了两周。在这个系统中，Velade恢复了dystrophin和dystrophin糖蛋白复合体成员的膜表达，并改善了营养不良的表型。在第二种方法中，我们用从DMD或BMD患者的肌肉活检中提取的复合外植体进行治疗。我们发现，抑制蛋白酶体途径上调了骨质疏松症患者外植体中肌营养不良蛋白、α-肌聚糖和β-肌营养不良蛋白的水平，而它增加了DMD患者外植体中肌营养不良蛋白糖蛋白复合体的蛋白水平。
Duchenne muscular dystrophy (DMD) and its milder allelic variant, Becker muscular dystrophy (BMD), result from mutations of the dystrophin gene and lead to progressive muscle deterioration. Enhanced activation of proteasomal degradation underlies critical steps in the pathogenesis of the DMD/BMD dystrophic process. Previously, we demonstrated that treatment with the proteasome inhibitor MG-132 rescues the cell membrane localization of dystrophin and the dystrophin glycoprotein complex in mdx mice, a natural genetic mouse model of DMD. The current work aims to thoroughly define the therapeutic potential in dystrophinopathies of Velcade, a drug that selectively blocks the ubiquitin-proteasome pathway. Velcade is particularly intriguing since it has been approved for the treatment of multiple myeloma. Therefore, its side effects in humans have been explored. Velcade effects were analyzed through two independent methodological approaches. First, we administered the drug systemically in mdx mice over a 2-week period. In this system, Velcade restores the membrane expression of dystrophin and dystrophin glycoprotein complex members and improves the dystrophic phenotype. In a second approach, we treated with the compound explants from muscle biopsies of DMD or BMD patients. We show that the inhibition of the proteasome pathway up-regulates dystrophin, alpha-sarcoglycan, and beta-dystroglycan protein levels in explants from BMD patients, whereas it increases the proteins of the dystrophin glycoprotein complex in DMD cases.
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影响因子：
45.3
作者：
Blaney, SM;Bernstein, M;Adamson, PC
通讯作者：
Adamson, PC
影响因子：
3.1
作者：
Silvia Repetto;M. Bado;P. Broda;G. Lucania;Emiliana Masetti;F. Sotgia;Ilaria Carbone;Antonio Pavan;Eduardo Bonilla;Giuseppe Cordone;M. Lisanti;Carlo Minetti
通讯作者：
Silvia Repetto;M. Bado;P. Broda;G. Lucania;Emiliana Masetti;F. Sotgia;Ilaria Carbone;Antonio Pavan;Eduardo Bonilla;Giuseppe Cordone;M. Lisanti;Carlo Minetti
影响因子：
15.9
作者：
Acharyya, Swarnali;Villalta, S. Armando;Guttridge, Denis C.
通讯作者：
Guttridge, Denis C.
影响因子：
3.5
作者：
Villalta, S. Armando;Nguyen, Hal X.;Tidball, James G.
通讯作者：
Tidball, James G.