Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, Delaware, United States of America.
PLoS One. 2013 Aug 16;8(8):e70288. doi: 10.1371/journal.pone.0070288. eCollection 2013.
Cerebral palsy (CP) is a static encephalopathy occurring when a lesion to the developing brain results in disordered movement and posture. Patients present with sometimes overlapping spastic, athetoid/dyskinetic, and ataxic symptoms. Spastic CP, which is characterized by stiff muscles, weakness, and poor motor control, accounts for ∼80% of cases. The detailed mechanisms leading to disordered movement in spastic CP are not completely understood, but clinical experience and recent studies suggest involvement of peripheral motor synapses. For example, it is recognized that CP patients have altered sensitivities to drugs that target neuromuscular junctions (NMJs), and protein localization studies suggest that NMJ microanatomy is disrupted in CP. Since CP originates during maturation, we hypothesized that NMJ disruption in spastic CP is associated with retention of an immature neuromotor phenotype later in life. Scoliosis patients with spastic CP or idiopathic disease were enrolled in a prospective, partially-blinded study to evaluate NMJ organization and neuromotor maturation. The localization of synaptic acetylcholine esterase (AChE) relative to postsynaptic acetylcholine receptor (AChR), synaptic laminin β2, and presynaptic vesicle protein 2 (SV2) appeared mismatched in the CP samples; whereas, no significant disruption was found between AChR and SV2. These data suggest that pre- and postsynaptic NMJ components in CP children were appropriately distributed even though AChE and laminin β2 within the synaptic basal lamina appeared disrupted. Follow up electron microscopy indicated that NMJs from CP patients appeared generally mature and similar to controls with some differences present, including deeper postsynaptic folds and reduced presynaptic mitochondria. Analysis of maturational markers, including myosin, syntrophin, myogenin, and AChR subunit expression, and telomere lengths, all indicated similar levels of motor maturation in the two groups. Thus, NMJ disruption in CP was found to principally involve components of the synaptic basal lamina and subtle ultra-structural modifications but appeared unrelated to neuromotor maturational status.
脑性瘫痪（CP）是一种在发育中的大脑受损时发生的静态脑病，导致运动和姿势障碍。患者表现出有时重叠的痉挛、手足徐动症/运动障碍和共济失调症状。痉挛性 CP 以肌肉僵硬、无力和运动控制不良为特征，占病例的约 80%。导致痉挛性 CP 运动障碍的详细机制尚未完全理解，但临床经验和最近的研究表明，周围运动突触参与其中。例如，人们认识到 CP 患者对靶向神经肌肉接头（NMJ）的药物有不同的敏感性，蛋白质定位研究表明 CP 中 NMJ 微解剖结构受到破坏。由于 CP 起源于成熟过程中，我们假设痉挛性 CP 中的 NMJ 破坏与生命后期保留不成熟的神经运动表型有关。患有痉挛性 CP 或特发性疾病的脊柱侧凸患者被纳入前瞻性、部分盲法研究中，以评估 NMJ 组织和神经运动成熟情况。CP 样本中突触乙酰胆碱酯酶（AChE）相对于突触后乙酰胆碱受体（AChR）、突触层粘连蛋白β2 和突触小泡蛋白 2（SV2）的定位似乎不匹配；而 AChR 和 SV2 之间没有发现明显的破坏。这些数据表明，CP 儿童的 NMJ 前体和后体成分即使在突触基底层内的 AChE 和层粘连蛋白β2 似乎被破坏的情况下，也得到了适当的分布。后续的电子显微镜检查表明，CP 患者的 NMJ 总体上看起来成熟，与对照组相似，但存在一些差异，包括更深的突触后褶皱和减少的突触前线粒体。对成熟标志物（包括肌球蛋白、连接蛋白、肌生成素和 AChR 亚基表达和端粒长度）的分析表明，两组的运动成熟水平相似。因此，CP 中的 NMJ 破坏主要涉及突触基底层的成分和细微的超微结构改变，但与神经运动成熟状态无关。
