A Drosophila model of oculopharyngeal muscular dystrophy reveals intrinsic toxicity of PABPN1
A Drosophila model of oculopharyngeal muscular dystrophy reveals intrinsic toxicity of PABPN1
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DOI：
10.1038/sj.emboj.7601117
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发表时间：
2006-05-17
期刊：
影响因子：
11.4
通讯作者：
Simonelig, Martine
中科院分区：
文献类型：
--
作者：
Chartier, Aymeric;Benoit, Beatrice;Simonelig, Martine
眼咽肌营养不良症 (OPMD) 是一种成人发病的综合征，其特征是特定肌肉进行性退化。 OPMD 是由编码核聚腺苷酸结合蛋白 1 (PABPN1) 的基因内的短 GCG 重复扩增引起的，该重复扩增延长了蛋白质中的 N 端聚丙氨酸束。突变的 PABPN1 在 OMPD 患者肌肉中聚集为核内含物。我们创建了 OPMD 的果蝇模型，它概括了人类疾病的特征：进行性肌肉退化，肌肉缺陷与纤维束中丙氨酸的数量成正比，以及 PABPN1 核包涵体的形成。引人注目的是，多聚丙氨酸束并不是肌肉退化所必需的，而 PABPN1 的另一个结构域、RNA 结合结构域及其在 RNA 结合中的功能是必需的。这表明 OPMD 不是由聚丙氨酸毒性引起的，而是由 PABPN1 的固有特性引起的。我们还鉴定了 OPMD 表型的几种抑制因子。这使我们的 OPMD 果蝇模型成为一种强大的体内测试，以了解疾病过程并开发新的治疗策略。
Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset syndrome characterized by progressive degeneration of particular muscles. OPMD is caused by short GCG repeat expansions within the gene encoding the nuclear poly(A)- binding protein 1 (PABPN1) that extend an N-terminal polyalanine tract in the protein. Mutant PABPN1 aggregates as nuclear inclusions in OMPD patient muscles. We have created a Drosophila model of OPMD that recapitulates the features of the human disorder: progressive muscle degeneration, with muscle defects proportional to the number of alanines in the tract, and formation of PABPN1 nuclear inclusions. Strikingly, the polyalanine tract is not absolutely required for muscle degeneration, whereas another domain of PABPN1, the RNA-binding domain and its function in RNA binding are required. This demonstrates that OPMD does not result from polyalanine toxicity, but from an intrinsic property of PABPN1. We also identify several suppressors of the OPMD phenotype. This establishes our OPMD Drosophila model as a powerful in vivo test to understand the disease process and develop novel therapeutic strategies.