近期，国际学术期刊《自噬》（Autophagy）发表了中科院上海生命科学研究院/上海交大医学院健康所、中科院干细胞生物学重点实验室乐卫东研究组的研究成果Rapamycin treatment augments motor neuron degeneration in SOD1G93A mouse model of amyotrophic lateral sclerosis。本项研究发现早期脊髓运动神经元内特异性的自噬水平升高，同时首次报道自噬激活剂雷帕霉素加速肌萎缩侧索硬化症（ALS）模型小鼠的发病，并初步探讨其可能机制。

ALS运动神经元内蛋白质异常聚集可能是导致神经元选择性死亡的重要机制。自噬作为胞内蛋白质降解的主要途径，是现在蛋白质聚集类疾病的研究热点之一。自噬可能通过降解胞内聚集的蛋白质起到神经保护作用；但同时过度激活或者自噬途径的不完整可能加速神经元的死亡。而自噬在ALS发病过程及运动神经元选择性死亡中所发挥的作用至今仍未有相关报道。

乐卫东课题组的科研助理张晓洁等科研人员利用经典的ALS转基因小鼠SOD1G93A小鼠，发现在转基因小鼠脊髓前角运动神经元内特异性自噬小体（AVs）数目增加，而且神经元轴突内增加要早于胞内，提示运动神经元内自噬水平的特异性改变。进一步利用经典的自噬激活剂雷帕霉素作用于转基因小鼠后发现，其能够加速疾病进程，促进小鼠的死亡。同时雷帕霉素能够加重运动神经元内线粒体损伤，激活凋亡的发生。更有意思的发现是，雷帕霉素在激活运动神经元内自噬的同时不能减少胞内SOD1蛋白的聚集，且伴有自噬通量标记p62蛋白的异常改变，结果提示ALS转基因小鼠内可能存在自噬通量的异常即自噬通量完整性的改变。

研究结果首次报道了自噬激活剂雷帕霉素对SOD1G93A转基因小鼠疾病进程的影响并探讨了其可能机制。首次提出ALS存在自噬完整性异常这一科学问题，为研究自噬与ALS及其他蛋白聚集性疾病发病之间的关系指明了新的方向。

原文出处：

Autophagy    DOI: 10.4161/auto.7.4.14541

Rapamycin treatment augments motor neuron degeneration in SOD1G93A mouse model of amyotrophic lateral sclerosis

Xiaojie Zhang, Liang Li, Sheng Chen, Dehua Yang, Yi Wang, Xin Zhang, Zheng Wang and Weidong Le

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 SOD1G93A 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.