Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Milan, Italy.
Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Neurology Unit, Via Francesco Sforza 35, 20122, Milan, Italy.
Acta Neuropathol. 2020 May;139(5):837-853. doi: 10.1007/s00401-020-02133-x. Epub 2020 Feb 17.
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.
在肌萎缩侧索硬化症（ALS）和脊髓性肌萎缩症（SMA）中，脊髓和脑桥下部运动神经元退化，但有些运动神经元亚型得以幸免，包括眼动神经元（OMN）。导致这种选择性退化的机制在很大程度上尚不清楚，但抗性和易感性运动神经元的分子特征明显不同，为神经元的弹性和敏感性提供了线索。在这里，我们证明健康的 OMN 与脊髓运动神经元相比，优先表达突触结合蛋白 13（SYT13）。在终末期 ALS 患者中，与对照组相比，SYT13 在 OMN 和剩余相对有弹性的脊髓运动神经元中均丰富。体外过表达 SYT13 可改善 ALS 和 SMA 患者运动神经元的存活并增加轴突长度。Syt13 的基因治疗可通过保护运动神经元和延迟肌肉失神经支配，使 ALS 小鼠的寿命延长 14%，使 SMA 小鼠的寿命延长 50%。SYT13 可减少运动神经元的内质网应激和细胞凋亡，无论是在体外还是体内。因此，SYT13 是一种可以保护运动神经元的弹性因子，也是跨运动神经元疾病的候选治疗靶点。
