Centre for Discovery Brain Sciences, College of Medicine and Veterinary Medicine, University of Edinburgh, Old Medical School, Teviot Place, Edinburgh, EH8 9XD, UK.
Molecular, Genetic and Population Health Sciences, Usher Institute, University of Edinburgh, Edinburgh, EH16 4UX, UK.
Skelet Muscle. 2022 Sep 12;12(1):22. doi: 10.1186/s13395-022-00305-9.
Spinal muscular atrophy (SMA) is a form of motor neuron disease affecting primarily children characterised by the loss of lower motor neurons (MNs). Breakdown of the neuromuscular junctions (NMJs) is an early pathological event in SMA. However, not all motor neurons are equally vulnerable, with some populations being lost early in the disease while others remain intact at the disease end-stage. A thorough understanding of the basis of this selective vulnerability will give critical insight into the factors which prohibit pathology in certain motor neuron populations and consequently help identify novel neuroprotective strategies.
To retrieve a comprehensive understanding of motor neuron susceptibility in SMA, we mapped NMJ pathology in 20 muscles from the Smn SMA mouse model and cross-compared these data with published data from three other commonly used mouse models. To gain insight into the molecular mechanisms regulating selective resilience and vulnerability, we analysed published RNA sequencing data acquired from differentially vulnerable motor neurons from two different SMA mouse models.
In the Smn mouse model of SMA, we identified substantial NMJ loss in the muscles from the core, neck, proximal hind limbs and proximal forelimbs, with a marked reduction in denervation in the distal limbs and head. Motor neuron cell body loss was greater at T5 and T11 compared with L5. We subsequently show that although widespread denervation is observed in each SMA mouse model (with the notable exception of the Taiwanese model), all models have a distinct pattern of selective vulnerability. A comparison of previously published data sets reveals novel transcripts upregulated with a disease in selectively resistant motor neurons, including genes involved in axonal transport, RNA processing and mitochondrial bioenergetics.
Our work demonstrates that the Smn mouse model shows a pattern of selective vulnerability which bears resemblance to the regional pathology observed in SMA patients. We found drastic differences in patterns of selective vulnerability across the four SMA mouse models, which is critical to consider during experimental design. We also identified transcript groups that potentially contribute to the protection of certain motor neurons in SMA mouse models.
脊髓性肌萎缩症（SMA）是一种影响主要为儿童的运动神经元疾病，其特征在于下运动神经元（MNs）的丧失。神经肌肉接头（NMJs）的破坏是 SMA 的早期病理事件。然而，并非所有运动神经元都同样易受影响，一些神经元在疾病早期就丧失了，而另一些则在疾病终末期仍然完好无损。对这种选择性易损性的基础有一个透彻的了解，将为了解哪些因素可以阻止某些运动神经元群体发生病变提供关键的见解，并有助于确定新的神经保护策略。
为了全面了解 SMA 中运动神经元的易感性，我们绘制了 Smn SMA 小鼠模型 20 块肌肉中的 NMJ 病理，并将这些数据与另外三种常用的小鼠模型的已发表数据进行了交叉比较。为了深入了解调节选择性恢复力和易损性的分子机制，我们分析了来自两种不同 SMA 小鼠模型的差异易损性运动神经元的已发表 RNA 测序数据。
在 Smn SMA 小鼠模型中，我们发现 NMJ 在核心、颈部、近端后肢和近端前肢的肌肉中大量丢失，而在远端肢体和头部则明显减少去神经支配。与 L5 相比，T5 和 T11 的运动神经元细胞体丢失更多。随后，我们发现尽管在每种 SMA 小鼠模型中都观察到广泛的去神经支配（台湾模型除外），但所有模型都有明显的选择性易损性模式。对以前发表的数据的比较揭示了与选择性抵抗运动神经元中疾病相关的上调新型转录本，包括参与轴突运输、RNA 处理和线粒体生物能的基因。
我们的工作表明，Smn 小鼠模型表现出与 SMA 患者观察到的区域性病理相似的选择性易损性模式。我们发现四种 SMA 小鼠模型之间的选择性易损性模式存在显著差异，这在实验设计中是至关重要的。我们还确定了潜在有助于 SMA 小鼠模型中某些运动神经元保护的转录组。
