Rapamycin treatment augments motor neuron degeneration in SOD1G93A mouse model of amyotrophic lateral sclerosis
Rapamycin treatment augments motor neuron degeneration in SOD1G93A mouse model of amyotrophic lateral sclerosis
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DOI：
10.4161/auto.7.4.14541
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发表时间：
2011-04-01
期刊：
影响因子：
13.3
通讯作者：
Le, Weidong
中科院分区：
文献类型：
--
作者：
Zhang, Xiaojie;Li, Liang;Le, Weidong
蛋白质错误折叠可能是肌萎缩侧索硬化症（ALS）的发病机制之一，但其具体机制尚不清楚。我们先前的研究表明，自噬在ALS小鼠模型中发生了改变。本研究系统研究了ALS小鼠自噬改变与运动神经元变性的关系。我们已经证明，自噬蛋白标志物LC 3-II在ALS小鼠的脊髓MN中显著且特异性地增加。电镜和免疫组化研究表明，ALS小鼠脊髓MN的营养不良轴突中自噬空泡明显积聚。所有这些变化在ALS小鼠中出现在90日龄时，ALS小鼠表现出适度的临床症状;并且在120日龄时变得突出。临床症状与MNs变性的进展相关。此外，我们发现p62/SQSTM 1在脊髓中进行性积累，表明在SOD 1（G93 A）小鼠中自噬通量受损的可能性。此外，令我们惊讶的是，我们发现用自噬增强剂雷帕霉素治疗加速了MN的变性，缩短了ALS小鼠的寿命，并且对SOD 1聚集体的积累没有明显的影响。此外，我们已经证明，雷帕霉素治疗ALS小鼠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，MN的选择性变性与自噬途径的损伤有关，并且雷帕霉素治疗可能通过ALS小鼠中的细胞凋亡和其他机制加剧病理过程。
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.