In amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), spinal and lower brainstem motor neurons degenerate, but some motor neuron subtypes are spared, including oculomotor neurons (OMNs). The mechanisms responsible for this selective degeneration are largely unknown, but the molecular signatures of resistant and vulnerable motor neurons are distinct and offer clues to neuronal resilience and susceptibility. Here, we demonstrate that healthy OMNs preferentially express Synaptotagmin 13 (SYT13) compared to spinal motor neurons. In end-stage ALS patients, SYT13 is enriched in both OMNs and the remaining relatively resilient spinal motor neurons compared to controls. Overexpression of SYT13 in ALS and SMA patient motor neurons in vitro improves their survival and increases axon lengths. Gene therapy with Syt13 prolongs the lifespan of ALS mice by 14% and SMA mice by 50% by preserving motor neurons and delaying muscle denervation. SYT13 decreases endoplasmic reticulum stress and apoptosis of motor neurons, both in vitro and in vivo. Thus, SYT13 is a resilience factor that can protect motor neurons and a candidate therapeutic target across motor neuron diseases.

中文翻译：

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Synaptotagmin 13对运动神经元疾病具有神经保护作用。

在肌萎缩性侧索硬化症（ALS）和脊髓性肌萎缩症（SMA）中，脊髓和下脑干运动神经元退化，但保留了一些运动神经元亚型，包括动眼神经元（OMN）。造成这种选择性变性的机制在很大程度上尚不清楚，但是抗性和脆弱的运动神经元的分子特征是截然不同的，并为神经元的适应性和敏感性提供了线索。在这里，我们证明健康的OMNs与脊髓运动神经元相比优先表达Synaptotagmin 13（SYT13）。与对照组相比，在晚期ALS患者中，SYT13富含OMNs和其余相对有弹性的脊髓运动神经元。SYT13在ALS和SMA患者运动神经元中的过度表达可提高其存活率并增加轴突长度。通过保留运动神经元并延迟肌肉神经支配，使用Syt13进行基因治疗可将ALS小鼠的寿命延长14％，将SMA小鼠的寿命延长50％。SYT13在体外和体内均可降低内质网应激和运动神经元凋亡。因此，SYT13是一种弹性因子，可以保护运动神经元和跨运动神经元疾病的候选治疗靶标。