Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada K1H 8L6.
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada K1H 8L6; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada K1H 8M5; Department of Medicine, University of Ottawa, Ottawa, ON, Canada K1H 8M5.
Neurobiol Dis. 2013 Jan;49:57-67. doi: 10.1016/j.nbd.2012.08.019. Epub 2012 Aug 30.
Spinal muscular atrophy (SMA) is a devastating childhood motor neuron disease caused by mutations and deletions within the survival motor neuron 1 (SMN1) gene. Although other tissues may be involved, motor neurons remain primary pathological targets, with loss of neuromuscular junctions (NMJs) representing an early and significant event in pathogenesis. Although defects in axonal outgrowth and pathfinding have been observed in cell culture and in lower organisms upon Smn depletion, developmental defects in mouse models have been less obvious. Here, we have employed the Smn(2B/-) mouse model to investigate NMJ remodelling during SMA pathology, induced reinnervation, and paralysis. We show that whilst NMJs are capable of remodelling during pathogenesis, there is a marked reduction in paralysis-induced remodelling and in the nerve-directed re-organisation of acetylcholine receptors. This reduction in remodelling potential could not be attributed to a decreased rate of axonal growth. Finally, we have identified a loss of terminal Schwann cells which could contribute to the defects in remodelling/maintenance observed. Our work demonstrates that there are specific defects in NMJ remodelling in an intermediate SMA mouse model, which could contribute to or underlie pathogenesis in SMA. The development of strategies that can promote the remodelling potential of NMJs may therefore be of significant benefit to SMA patients.
脊髓性肌萎缩症（SMA）是一种毁灭性的儿童运动神经元疾病，由生存运动神经元 1（SMN1）基因的突变和缺失引起。尽管其他组织可能也会受到影响，但运动神经元仍然是主要的病理靶标，神经肌肉接头（NMJs）的丧失是发病机制中的一个早期和重要事件。尽管在 Smn 耗竭的细胞培养和低等生物中观察到轴突生长和寻路缺陷，但在小鼠模型中发育缺陷不太明显。在这里，我们使用 Smn(2B/-)小鼠模型来研究 SMA 病理过程中的 NMJ 重塑、再支配和瘫痪。我们表明，虽然 NMJs 在发病过程中能够进行重塑，但在瘫痪诱导的重塑和乙酰胆碱受体的神经导向重新组织方面，显著减少。这种重塑潜力的降低不能归因于轴突生长速度的降低。最后，我们发现终末施万细胞丢失，这可能导致观察到的重塑/维持缺陷。我们的工作表明，在中间型 SMA 小鼠模型中存在 NMJ 重塑的特定缺陷，这可能导致或成为 SMA 发病机制的基础。因此，开发能够促进 NMJ 重塑潜力的策略可能对 SMA 患者具有重要意义。
