Nuclear speckles are involved in nuclear aggregation of PABPN1 and in the pathophysiology of oculopharyngeal muscular dystrophy
Nuclear speckles are involved in nuclear aggregation of PABPN1 and in the pathophysiology of oculopharyngeal muscular dystrophy
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DOI：
10.1016/j.nbd.2011.12.052
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发表时间：
2012-04-01
影响因子：
6.1
通讯作者：
Berciano, Maria T.
中科院分区：
文献类型：
--
作者：
Bengoechea, Rocio;Tapia, Olga;Berciano, Maria T.
核斑点是参与前体mRNA加工因子的组装、递送和再循环以及前体mRNA的转录后加工的重要核隔室。眼咽型肌营养不良症（OPMD）是由多聚（A）结合蛋白核1（PABPN 1）中多聚丙氨酸束的小幅扩张引起的。扩展的PABPN 1聚集成骨骼肌纤维中的核内包涵体（INI）是OPMD的病理标志。在这项研究中，我们分析了OPMD患者的肌纤维和人成肌细胞的原代培养物中的核斑点和IN之间的关系，以及前者对后者生物发生的贡献。虽然核斑点集中snRNP剪接因子和PABPN 1在对照肌纤维，他们是耗尽的PABPN 1，并出现密切相关的肌纤维OPMD患者的INI。在表达野生型GFP-PABPN 1或扩增的GFP-PABPN 1 - 17 ala的人成肌细胞中诱导INI形成表明PABPN 1蛋白的初始聚集及其随后在INI中的生长发生在核斑点的边缘。此外，INN的生长逐渐消耗PABPN 1蛋白和poly（A）RNA从核斑点，虽然这些核隔室的存在被保存。在培养的成肌细胞中的延时实验证实核斑点是PABPN 1包涵体的生物发生位点。鉴于核斑点在前mRNA转录后加工中的功能重要性，肌纤维中这些核隔室的INI依赖性分子重组可能导致核运输和多聚腺苷酸化mRNA加工的严重功能障碍，从而导致OPMD的分子病理生理学。我们的结果强调了核斑点作为神经肌肉疾病核靶点的潜在重要性。(C)2012 Elsevier Inc. All rights reserved.
Nuclear speckles are essential nuclear compartments involved in the assembly, delivery and recycling of pre-mRNA processing factors, and in the post-transcriptional processing of pre-mRNAs. Oculopharyngeal muscular dystrophy (OPMD) is caused by a small expansion of the polyalanine tract in the poly(A)-binding protein nuclear 1 (PABPN1). Aggregation of expanded PABPN1 into intranuclear inclusions (INIs) in skeletal muscle fibers is the pathological hallmark of OPMD. In this study what we have analyzed in muscle fibers of OPMD patients and in primary cultures of human myoblasts are the relationships between nuclear speckles and IN's, and the contribution of the former to the biogenesis of the latter. While nuclear speckles concentrate snRNP splicing factors and PABPN1 in control muscle fibers, they are depleted of PABPN1 and appear closely associated with INIs in muscle fibers of OPMD patients. The induction of INI formation in human myoblasts expressing either wild type GFP-PABPN1 or expanded GFP-PABPN1-17ala demonstrates that the initial aggregation of PABPN1 proteins and their subsequent growth in INIs occurs at the edges of the nuclear speckles. Moreover, the growing of INN gradually depletes PABPN1 proteins and poly(A) RNA from nuclear speckles, although the existence of these nuclear compartments is preserved. Time-lapse experiments in cultured myoblasts confirm nuclear speckles as biogenesis sites of PABPN1 inclusions. Given the functional importance of nuclear speckles in the post-transcriptional processing of pre-mRNAs, the INI-dependent molecular reorganization of these nuclear compartments in muscle fibers may cause a severe dysfunction in nuclear trafficking and processing of polyadenylated mRNAs, thereby contributing to the molecular pathophysiology of OPMD. Our results emphasize the potential importance of nuclear speckles as nuclear targets of neuromuscular disorders. (C) 2012 Elsevier Inc. All rights reserved.