Marinesco-Sjogren syndrome protein SIL1 regulates motor neuron subtype-selective ER stress in ALS
Marinesco-Sjogren syndrome protein SIL1 regulates motor neuron subtype-selective ER stress in ALS
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DOI：
10.1038/nn.3903
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发表时间：
2015-02-01
影响因子：
25
通讯作者：
Saxena, Smita
中科院分区：
文献类型：
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作者：
de L'Etang, Audrey Filezac;Maharjan, Niran;Saxena, Smita
肌萎缩侧索硬化（ALS）中运动神经元亚型选择性内质网（ER）应激和相关轴突病理的机制尚不清楚。在这里，我们表明运动神经元亚型之间的内质网分子环境是不同的，具有特征特征。我们发现在marinesco - shjogren综合征（MSS）中发生突变的cochaperone SILL在抗病性慢运动神经元中强烈表达，而在内质网应激倾向的快速疲劳运动神经元中不表达。在小鼠MSS模型中，我们证明了运动神经元内质网稳态受损是对SIL1功能丧失的反应。ALS小鼠模型中单个功能性Sill等位基因（SOD1-G93A）的缺失会增强内质网应激并加剧ALS病理。在SOD1-G93A小鼠中，易受伤害的快速疲劳运动神经元中SIL1水平逐渐和选择性地降低。从机制上讲，SIL1水平的降低与快速疲劳运动神经元的兴奋性降低有关，进一步影响特异性ER伴侣的表达。腺相关病毒介导的SIL1传递至家族性ALS运动神经元可恢复内质网稳态，延缓肌肉去神经支配，延长生存期。
Mechanisms underlying motor neuron subtype selective endoplasmic reticulum (ER) stress and associated axonal pathology in amyotrophic lateral sclerosis (ALS) remain unclear. Here we show that the molecular environment of the ER between motor neuron subtypes is distinct, with characteristic signatures. We identify cochaperone SILL mutated in Marinesco-Sjogren syndrome (MSS), as being robustly expressed in disease-resistant slow motor neurons but not in ER stress prone fast-fatigable motor neurons. In a mouse model of MSS, we demonstrate impaired ER homeostasis in motor neurons in response to loss of SIL1 function. Loss of a single functional Sill allele in an ALS mouse model (SOD1-G93A) enhanced ER stress and exacerbated ALS pathology. In SOD1-G93A mice, SIL1 levels were progressively and selectively reduced in vulnerable fast-fatigable motor neurons. Mechanistically, reduction in SIL1 levels was associated with lowered excitability of fast-fatigable motor neurons, further influencing expression of specific ER chaperones. Adeno-associated virus mediated delivery of SIL1 to familial ALS motor neurons restored ER homeostasis, delayed muscle denervation and prolonged survival.