Aberrant neuromuscular junctions and delayed terminal muscle fiber maturation in α-dystroglycanopathies
Aberrant neuromuscular junctions and delayed terminal muscle fiber maturation in α-dystroglycanopathies
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DOI：
10.1093/hmg/ddl045
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发表时间：
2006-04-15
影响因子：
3.5
通讯作者：
Toda, T
中科院分区：
文献类型：
--
作者：
Taniguchi, M;Kurahashi, H;Toda, T
最近的研究表明，α-DG的翻译后修饰(α-DG)与某些称为继发性α-营养不良的先天性肌营养不良症(α-DGpathies)之间存在关联。福山型先天性肌营养不良症(FCMD)被归类为继发性α-DG病，因为相关基因fukutin是α-DG的糖基转移酶。为了研究继发性α-DG病变的病理生理学，我们对FCMD患者骨骼肌中的基因表达进行了分析。基因芯片分析和实时定量聚合酶链式反应显示，FCMD肌纤维中发育调控基因，包括肌球蛋白重链(Myosin Heavy Chain，MYH)和成肌转录因子(MyoD，Mygenin，MRF4)的表达与营养不良和活跃的肌肉再生不一致，而更多地与成熟停滞有关。FCMD骨骼肌主要含有未成熟的2C型纤维，未成熟型MYH阳性。这些特征不同于Duchenne肌营养不良症，提示除了营养不良外，还有另一种机制导致了FCMD骨骼肌病变。免疫组织化学分析显示形态异常的神经肌肉接头(NMJ)缺乏MRF4共定位。低糖基化的α-DG表明缺乏聚集，在FCMD和肌营养不良症小鼠中，乙酰胆碱受体(AChR)聚集受到损害，这是继发性α-DG病变的另一个模型。电子显微镜显示异常的NMJ和神经末梢，以及成熟缺陷的肌管。功能分析显示，阿尔茨海默病的NMJ的微小终板电位降低，对d-Tubocurarine的敏感性更高，提示NMJ的异常或塌陷形成。由于α-DG聚集和随后的AChR聚集对NMJ的形成至关重要，在继发性的α-DG疾病中，α-DG的低糖基化导致NMJ的异常形成和肌肉的终末成熟延迟。虽然骨骼肌纤维的严重坏死性变性或萎缩是先天性肌营养不良的主要原因，但肌肉纤维成熟延迟也是继发性α-DG病的病因。
Recent studies have revealed an association between post-translational modification of alpha-dystroglycan (alpha-DG) and certain congenital muscular dystrophies known as secondary alpha-dystroglycanopathies (alpha-DGpathies). Fukuyama-type congenital muscular dystrophy (FCMD) is classified as a secondary alpha-DGpathy because the responsible gene, fukutin, is a putative glycosyltransferase for alpha-DG. To investigate the pathophysiology of secondary alpha-DGpathies, we profiled gene expression in skeletal muscle from FCMD patients. cDNA microarray analysis and quantitative real-time polymerase chain reaction showed that expression of developmentally regulated genes, including myosin heavy chain (MYH) and myogenic transcription factors (MRF4, myogenin and MyoD), in FCMD muscle fibers is inconsistent with dystrophy and active muscle regeneration, instead more of implicating maturational arrest. FCMD skeletal muscle contained mainly immature type 2C fibers positive for immature-type MYH. These characteristics are distinct from Duchenne muscular dystrophy, suggesting that another mechanism in addition to dystrophy accounts for the FCMD skeletal muscle lesion. Immunohistochemical analysis revealed morphologically aberrant neuromuscular junctions (NMJs) lacking MRF4 co-localization. Hypoglycosylated alpha-DG indicated a lack of aggregation, and acetylcholine receptor (AChR) clustering was compromised in FCMD and the myodystrophy mouse, another model of secondary alpha-DGpathy. Electron microscopy showed aberrant NMJs and neural terminals, as well as myotubes with maturational defects. Functional analysis of NMJs of alpha-DGpathy showed decreased miniature endplate potential and higher sensitivities to d-Tubocurarine, suggesting aberrant or collapsed formation of NMJs. Because alpha-DG aggregation and subsequent clustering of AChR are crucial for NMJ formation, hypoglycosylation of alpha-DG results in aberrant NMJ formation and delayed muscle terminal maturation in secondary alpha-DGpathies. Although severe necrotic degeneration or wasting of skeletal muscle fibers is the main cause of congenital muscular dystrophies, maturational delay of muscle fibers also underlies the etiology of secondary alpha-DGpathies.