Antiprion drugs 6-aminophenanthridine and guanabenz reduce PABPN1 toxicity and aggregation in oculopharyngeal muscular dystrophy.
Antiprion drugs 6-aminophenanthridine and guanabenz reduce PABPN1 toxicity and aggregation in oculopharyngeal muscular dystrophy.
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DOI：
10.1002/emmm.201000109
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发表时间：
2011-01
影响因子：
11.1
通讯作者：
Simonelig, Martine
中科院分区：
文献类型：
--
作者：
Barbezier, Nicolas;Chartier, Aymeric;Bidet, Yannick;Buttstedt, Anja;Voisset, Cecile;Galons, Herve;Blondel, Marc;Schwarz, Elisabeth;Simonelig, Martine
眼咽肌营养不良症（OPMD）是一种以特定肌肉进行性变性为特征的成人发病综合征。OPMD是由多聚（A）结合蛋白核1（PABPN 1）中的多聚丙氨酸区的延伸引起的。在患病的肌肉中形成不溶性核内含物。我们已经产生了一个果蝇模型OPMD，概括的功能障碍。在这里，我们表明，抗朊病毒药物6-aminophenanthridine（6AP）和胍那苄乙酸（GA），防止形成淀粉样纤维的朊病毒蛋白在细胞模型中，减轻OPMD表型在果蝇，包括肌肉变性和核包涵体的形成。大核糖体RNA及其在蛋白质折叠中的活性最近被鉴定为6AP和GA的特异性细胞靶点。我们发现，核糖体DNA位点的缺失减少OPMD表型和协同作用与亚有效剂量的6AP。在一个互补的方法，我们证明，核糖体RNA加速体外原纤维形成的PABPN 1 N-末端结构域。这些结果揭示了核糖体RNA在不同蛋白质聚集障碍中的保守作用，并确定6AP和GA为一般的抗聚集分子。
Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset syndrome characterized by progressive degeneration of specific muscles. OPMD is caused by extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). Insoluble nuclear inclusions form in diseased muscles. We have generated a Drosophila model of OPMD that recapitulates the features of the disorder. Here, we show that the antiprion drugs 6-aminophenanthridine (6AP) and guanabenz acetate (GA), which prevent formation of amyloid fibers by prion proteins in cell models, alleviate OPMD phenotypes in Drosophila, including muscle degeneration and nuclear inclusion formation. The large ribosomal RNA and its activity in protein folding were recently identified as a specific cellular target of 6AP and GA. We show that deletions of the ribosomal DNA locus reduce OPMD phenotypes and act synergistically with sub-effective doses of 6AP. In a complementary approach, we demonstrate that ribosomal RNA accelerates in vitro fibril formation of PABPN1 N-terminal domain. These results reveal the conserved role of ribosomal RNA in different protein aggregation disorders and identify 6AP and GA as general anti-aggregation molecules.
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