Nuclear inclusions in oculopharyngeal muscular dystrophy consist of poly(A) binding protein 2 aggregates which sequester poly(A) RNA
Nuclear inclusions in oculopharyngeal muscular dystrophy consist of poly(A) binding protein 2 aggregates which sequester poly(A) RNA
复制标题
DOI：
10.1093/oxfordjournals.hmg.a018924
复制
发表时间：
2000-09-22
影响因子：
3.5
通讯作者：
Carmo-Fonseca, M
中科院分区：
文献类型：
--
作者：
Calado, A;Tomé, FMS;Carmo-Fonseca, M
眼咽肌营养不良症是一种以眼睑下垂、吞咽困难和近端肢体无力为特征的成人发病性疾病。该疾病的常染色体显性形式由PABP 2基因中的短（GCG）（8-13）扩增引起。该基因编码多聚腺苷酸结合蛋白2（PABP 2），这是一种丰富的核蛋白，以高亲和力结合新生的多聚腺苷酸尾，刺激它们的延伸并控制它们的长度。在这项工作中，我们报告，PABP 2检测丝状核包涵体，这是病理霍尔标记OPMD。使用免疫电子显微镜和荧光共聚焦显微镜，OPMD特异性核包涵体出现抗PABP 2抗体装饰。此外，内含物被标记有针对泛素和蛋白酶体亚基的抗体，并含有PABP 2的形式，其比分散在核质中的蛋白质更耐盐提取。这表明PABP 2中的聚丙氨酸扩增诱导蛋白质错误折叠和聚集成不溶性内含物，类似于CAG/聚谷氨酰胺扩增引起的神经退行性疾病中的事件。OPMD和正常成肌细胞的poly（A）尾长无明显差异，但核内含物可隔离poly（A）RNA。这提出了在OPMD中PABP 2蛋白中的聚丙氨酸扩增可能干扰聚（A）RNA的细胞运输的可能性。
Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disease characterized by progressive eyelid drooping, swallowing difficulties and proximal limb weakness. The autosomal dominant form of the disease is caused by short (GCG)(8-13) expansions in the PABP2 gene. This gene encodes the poly(A) binding protein 2 (PABP2), an abundant nuclear protein that binds with high affinity to nascent poly(A) tails, stimulating their extension and controlling their length. In this work we report that PABP2 is detected in filamentous nuclear inclusions, which are the pathological hall mark of OPMD. Using both immunoelectron microscopy and fluorescence confocal microscopy, the OPMD-specific nuclear inclusions appeared decorated by anti-PABP2 antibodies. In addition, the inclusions were labeled with antibodies directed against ubiquitin and the subunits of the proteasome and contained a form of PABP2 that was more resistant to salt extraction than the protein dispersed in the nucleoplasm. This suggests that the polyalanine expansions in PABP2 induce a misfolding and aggregation of the protein into insoluble inclusions, similarly to events in neurodegenerative diseases caused by CAG/polyglutamine expansions. No significant differences were observed in the steady-state poly(A) tail length in OPMD and normal myoblasts, However, the nuclear inclusions were shown to sequester poly(A) RNA. This raises the possibility that in OPMD the polyalanine expansions in the PABP2 protein may interfere with the cellular traffic of poly(A) RNA.