Endplate denervation correlates with Nogo-A muscle expression in amyotrophic lateral sclerosis patients.
Endplate denervation correlates with Nogo-A muscle expression in amyotrophic lateral sclerosis patients.
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DOI：
10.1002/acn3.179
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发表时间：
2015-04
影响因子：
5.3
通讯作者：
Hantai, Daniel
中科院分区：
文献类型：
--
作者：
Bruneteau, Gaelle;Bauche, Stephanie;de Aguilar, Jose Luis Gonzalez;Brochier, Guy;Mandjee, Nathalie;Tanguy, Marie-Laure;Hussain, Ghulam;Behin, Anthony;Khiami, Frederic;Sariali, Elhadi;Hell-Remy, Caroline;Salachas, Francois;Pradat, Pierre-Francois;Lacomblez, Lucette;Nicole, Sophie;Fontaine, Bertrand;Fardeau, Michel;Loeffler, Jean-Philippe;Meininger, Vincent;Fournier, Emmanuel;Koenig, Jeanine;Hantai, Daniel
肌萎缩性侧索硬化症（ALS）小鼠模型的数据显示，神经肌肉连接（NMJs）早期形态学改变，神经肌肉接触丧失。神经突生长抑制剂Nogo-A在肌肉中的过度表达可能在终板神经支配的丧失中起作用。我们使用共聚焦显微镜和电子显微镜研究了9例ALS患者（5例早期患者和4例长期幸存者）肌肉样本中NMJs的结构。我们将形态学结果与临床和电生理数据以及Nogo-A肌肉表达水平相关联。3/9 ALS患者神经肌肉传递表面肌电图评估异常。在共聚焦显微镜下，几乎所有NMJs （n = 430）的突触后结构都发生了形态学改变。19.7%的NMJs完全失神经（突触沟槽碎片化，神经末梢轮廓缺失）。末梢轴突分枝稀疏，56.8%受支配的NMJs表现出典型的再神经支配模式。终末雪旺细胞（TSC）形态发生改变，胞质发生广泛变化。在某些情况下，可以看到突触间隙中明显的TSCs侵入，显著减少了神经肌肉传递的突触表面。最后，肌肉中Nogo-A的高水平表达与NMJ去神经支配程度的增加和负功能结果显著相关。我们的研究结果支持了一种假设，即NMJs的形态改变存在于疾病的早期，可能是ALS患者功能性运动障碍的重要原因。Nogo-A的肌肉表达与NMJ去神经支配有关，因此构成减缓疾病进展的治疗靶点。
Data from mouse models of amyotrophic lateral sclerosis (ALS) suggest early morphological changes in neuromuscular junctions (NMJs), with loss of nerve–muscle contact. Overexpression of the neurite outgrowth inhibitor Nogo-A in muscle may play a role in this loss of endplate innervation. We used confocal and electron microscopy to study the structure of the NMJs in muscle samples collected from nine ALS patients (five early-stage patients and four long-term survivors). We correlated the morphological results with clinical and electrophysiological data, and with Nogo-A muscle expression level. Surface electromyography assessment of neuromuscular transmission was abnormal in 3/9 ALS patients. The postsynaptic apparatus was morphologically altered for almost all NMJs (n = 430) analyzed using confocal microscopy. 19.7% of the NMJs were completely denervated (fragmented synaptic gutters and absence of nerve terminal profile). The terminal axonal arborization was usually sparsely branched and 56.8% of innervated NMJs showed a typical reinnervation pattern. Terminal Schwann cell (TSC) morphology was altered with extensive cytoplasmic processes. A marked intrusion of TSCs in the synaptic cleft was seen in some cases, strikingly reducing the synaptic surface available for neuromuscular transmission. Finally, high-level expression of Nogo-A in muscle was significantly associated with higher extent of NMJ denervation and negative functional outcome. Our results support the hypothesis that morphological alterations of NMJs are present from early-stage disease and may significantly contribute to functional motor impairment in ALS patients. Muscle expression of Nogo-A is associated with NMJ denervation and thus constitutes a therapeutic target to slow disease progression.
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影响因子：
5.3
作者：
Fischer, LR;Culver, DG;Glass, JD
通讯作者：
Glass, JD
影响因子：
3.5
作者：
Bros-Facer, Virginie;Krull, David;Greensmith, Linda
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Greensmith, Linda
影响因子：
4.4
作者：
Cedarbaum, JM;Stambler, N;Nakanishi, A
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Nakanishi, A
影响因子：
25
作者：
Pun, S;Santos, AF;Caroni, P
通讯作者：
Caroni, P
影响因子：
3.4
作者：
KILLIAN, JM;WILFONG, AA;BOLAND, D
通讯作者：
BOLAND, D