Synaptic defects in type I spinal muscular atrophy in human development
Synaptic defects in type I spinal muscular atrophy in human development
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DOI：
10.1002/path.4080
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发表时间：
2013-01-01
影响因子：
7.3
通讯作者：
Tizzano, Eduardo F.
中科院分区：
文献类型：
--
作者：
Martinez-Hernandez, Rebeca;Bernal, Sara;Tizzano, Eduardo F.
儿童脊髓性肌萎缩症是一种常染色体隐性遗传性神经肌肉疾病，由运动神经元生存1基因的改变引起，该基因触发脊髓内运动神经元的变性。脊髓性肌萎缩症是婴儿和幼儿期第二常见的严重遗传性疾病。在最严重的情况下（I型），这种疾病出现在生命的最初几个月，表明胎儿发育有缺陷。然而，目前尚不清楚运动神经元、神经肌肉接头和肌肉在疾病的神经病理学中如何相互作用。我们报告了对照组和脊髓性肌萎缩症产前和产后人类样本中神经肌肉接头的突触前和突触后装置的结构。共聚焦和电子显微镜研究的定性和定量数据显示，在产前I型脊髓性肌萎缩症样本的运动终板的乙酰胆碱受体聚集，异常preterminal积累的囊泡，和异常的超微结构的神经末梢的变化。预测发展较轻II型疾病的胎仔与对照组的外观相似。出生后的肌肉I型脊髓性肌萎缩症患者表现出持续的胎儿亚单位的乙酰胆碱受体，这表明在成熟的神经肌肉接头的延迟。我们观察到，病理严重形式的疾病开始在胎儿发育和缺陷，在维持初始神经支配是一个早期发现的神经肌肉功能障碍。这些结果将提高我们对脊髓性肌萎缩症发病机制的理解，并有助于确定可能的症状前治疗这种疾病的目标。版权所有（C）2012大不列颠和爱尔兰病理学会。出版社：John Wiley & Sons，Ltd
Childhood spinal muscular atrophy is an autosomal recessive neuromuscular disorder caused by alterations in the Survival Motor Neuron 1 gene that triggers degeneration of motor neurons within the spinal cord. Spinal muscular atrophy is the second most common severe hereditary disease of infancy and early childhood. In the most severe cases (type I), the disease appears in the first months of life, suggesting defects in fetal development. However, it is not yet known how motor neurons, neuromuscular junctions, and muscle interact in the neuropathology of the disease. We report the structure of presynaptic and postsynaptic apparatus of the neuromuscular junctions in control and spinal muscular atrophy prenatal and postnatal human samples. Qualitative and quantitative data from confocal and electron microscopy studies revealed changes in acetylcholine receptor clustering, abnormal preterminal accumulation of vesicles, and aberrant ultrastructure of nerve terminals in the motor endplates of prenatal type I spinal muscular atrophy samples. Fetuses predicted to develop milder type II disease had a similar appearance to controls. Postnatal muscle of type I spinal muscular atrophy patients showed persistence of the fetal subunit of acetylcholine receptors, suggesting a delay in maturation of neuromuscular junctions. We observed that pathology in the severe form of the disease starts in fetal development and that a defect in maintaining the initial innervation is an early finding of neuromuscular dysfunction. These results will improve our understanding of the spinal muscular atrophy pathogenesis and help to define targets for possible presymptomatic therapy for this disease. Copyright (C) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.