Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM F-75013, Paris, France ; APHP, Hôpital Pitié-Salpêtrière, Département des Maladies du Système Nerveux, Centre référent SLA Paris, France ; APHP, INSERM, ICM, Centre d'Investigation Clinique Pitié Neurosciences, CIC-1422, Département des Maladies du Système Nerveux, Hôpital Pitié-Salpêtrière Paris, France.
Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM F-75013, Paris, France.
Ann Clin Transl Neurol. 2015 Apr;2(4):362-72. doi: 10.1002/acn3.179. Epub 2015 Feb 16.
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.
肌萎缩侧索硬化症（ALS）的小鼠模型数据表明，神经肌肉接头（NMJ）的早期形态变化伴有神经肌肉接触丧失。肌肉中神经生长抑制因子 Nogo-A 的过度表达可能在这种终板神经支配丧失中发挥作用。
我们使用共聚焦和电子显微镜研究了从 9 名 ALS 患者（5 名早期患者和 4 名长期幸存者）采集的肌肉样本中 NMJ 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。
表面肌电图评估显示 3/9 的 ALS 患者神经肌肉传递异常。使用共聚焦显微镜分析，几乎所有 NMJ（n=430）的突触后装置形态发生改变。19.7%的 NMJ 完全失神经支配（突触小槽碎裂和神经末梢形态缺失）。终末轴突树突通常分支稀疏，56.8%的神经支配 NMJ 显示出典型的再支配模式。终末施万细胞（TSC）形态发生改变，细胞质突起广泛。在某些情况下，TSC 明显侵入突触间隙，显著减少了用于神经肌肉传递的突触表面积。最后，肌肉中 Nogo-A 的高水平表达与 NMJ 失神经支配的程度更高和功能不良的负性结果显著相关。
我们的研究结果支持这样一种假说，即 NMJ 的形态改变存在于疾病早期，并可能显著导致 ALS 患者的运动功能障碍。肌肉中 Nogo-A 的表达与 NMJ 失神经支配相关，因此构成了减缓疾病进展的治疗靶点。
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