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雷帕霉素治疗增强肌萎缩侧索硬化症 SOD1(G93A)小鼠模型中的运动神经元变性。

Rapamycin treatment augments motor neuron degeneration in SOD1(G93A) mouse model of amyotrophic lateral sclerosis.

机构信息

The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China.

出版信息

Autophagy. 2011 Apr;7(4):412-25. doi: 10.4161/auto.7.4.14541. Epub 2011 Apr 1.

Abstract

Aberrant protein misfolding may contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS) but the detailed mechanisms are largely unknown. Our previous study has shown that autophagy is altered in the mouse model of ALS. In the present study, we systematically investigated the correlation of the autophagic alteration with the motor neurons (MNs) degeneration in the ALS mice. We have demonstrated that the autophagic protein marker LC3-II is markedly and specifically increased in the spinal cord MNs of the ALS mice. Electron microscopy and immunochemistry studies have shown that autophagic vacuoles are significantly accumulated in the dystrophic axons of spinal cord MNs of the ALS mice. All these changes in the ALS mice appear at the age of 90 d when the ALS mice display modest clinical symptoms; and they become prominent at the age of 120 d. The clinical symptoms are correlated with the progression of MNs degeneration. Moreover, we have found that p62/SQSTM1 is accumulated progressively in the spinal cord, indicating that the possibility of impaired autophagic flux in the SOD1(G93A) mice. Furthermore, to our surprise, we have found that treatment with autophagy enhancer rapamycin accelerates the MNs degeneration, shortens the life span of the ALS mice, and has no obvious effects on the accumulation of SOD1 aggregates. In addition, we have demonstrated that rapamycin treatment in the ALS mice causes more severe mitochondrial impairment, higher Bax levels and greater caspase-3 activation. These findings suggest that selective degeneration of MNs is associated with the impairment of the autophagy pathway and that rapamycin treatment may exacerbate the pathological processing through apoptosis and other mechanisms in the ALS mice.

摘要

错误折叠的蛋白质可能导致肌萎缩侧索硬化症(ALS)的发病机制,但详细机制在很大程度上尚不清楚。我们之前的研究表明,自噬在 ALS 小鼠模型中发生改变。在本研究中,我们系统地研究了自噬改变与 ALS 小鼠运动神经元(MNs)变性之间的相关性。我们已经证明,自噬蛋白标志物 LC3-II 在 ALS 小鼠的脊髓 MNs 中明显且特异性增加。电子显微镜和免疫组织化学研究表明,自噬空泡在 ALS 小鼠的脊髓 MN 变性轴突中明显积累。这些在 ALS 小鼠中的变化出现在 90 日龄时,此时 ALS 小鼠出现轻微的临床症状;并且在 120 日龄时变得明显。临床症状与 MNs 变性的进展相关。此外,我们发现 p62/SQSTM1 在脊髓中逐渐积累,表明 SOD1(G93A) 小鼠中自噬流受损的可能性。此外,令我们惊讶的是,我们发现自噬增强剂雷帕霉素的治疗加速了 MNs 的变性,缩短了 ALS 小鼠的寿命,并且对 SOD1 聚集体的积累没有明显影响。此外,我们已经证明,雷帕霉素处理在 ALS 小鼠中导致更严重的线粒体损伤、更高的 Bax 水平和更大的 caspase-3 激活。这些发现表明,MNs 的选择性变性与自噬途径的损伤有关,雷帕霉素治疗可能通过凋亡和其他机制在 ALS 小鼠中加重病理过程。

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