Synaptotagmin 13 is neuroprotective across motor neuron diseases
Synaptotagmin 13 is neuroprotective across motor neuron diseases
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DOI：
10.1007/s00401-020-02133-x
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发表时间：
2020-02-17
影响因子：
12.7
通讯作者：
Corti, S.
中科院分区：
文献类型：
--
作者：
Nizzardo, M.;Taiana, M.;Corti, S.
在肌萎缩侧索硬化症（ALS）和脊髓性肌萎缩症（SMA）中，脊髓和下脑干运动神经元退化，但一些运动神经元亚型幸免，包括眼神经元（OMN）。负责这种选择性变性的机制在很大程度上是未知的，但抵抗和脆弱的运动神经元的分子特征是不同的，并提供神经元的弹性和易感性的线索。在这里，我们表明，健康的OMNs优先表达突触结合蛋白13（SYT13）相比，脊髓运动神经元。在终末期ALS患者中，与对照组相比，SYT13在OMN和剩余的相对有弹性的脊髓运动神经元中富集。体外ALS和SMA患者运动神经元中SYT13的过表达改善了它们的存活并增加了轴突长度。Syt13基因治疗通过保留运动神经元和延迟肌肉去神经，使ALS小鼠的寿命延长了14%，SMA小鼠的寿命延长了50%。SYT13降低内质网应激和运动神经元的凋亡，在体外和体内。因此，SYT13是可以保护运动神经元的弹性因子，并且是运动神经元疾病的候选治疗靶点。
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.