Departments of Neurology and Pathology and Cell Biology, Columbia University, New York, New York 10032, USA.
J Neurosci. 2011 Feb 9;31(6):2125-35. doi: 10.1523/JNEUROSCI.5519-10.2011.
Axon degeneration is a hallmark of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Such degeneration is not a passive event but rather an active process mediated by mechanisms that are distinct from the canonical pathways of programmed cell death that mediate destruction of the cell soma. Little is known of the diverse mechanisms involved, particularly those of retrograde axon degeneration. We have previously observed in living animal models of degeneration in the nigrostriatal projection that a constitutively active form of the kinase, myristoylated Akt (Myr-Akt), demonstrates an ability to suppress programmed cell death and preserve the soma of dopamine neurons. Here, we show in both neurotoxin and physical injury (axotomy) models that Myr-Akt is also able to preserve dopaminergic axons due to suppression of acute retrograde axon degeneration. This cellular phenotype is associated with increased mammalian target of rapamycin (mTor) activity and can be recapitulated by a constitutively active form of the small GTPase Rheb, an upstream activator of mTor. Axon degeneration in these models is accompanied by the occurrence of macroautophagy, which is suppressed by Myr-Akt. Conditional deletion of the essential autophagy mediator Atg7 in adult mice also achieves striking axon protection in these acute models of retrograde degeneration. The protection afforded by both Myr-Akt and Atg7 deletion is robust and lasting, because it is still observed as protection of both axons and dopaminergic striatal innervation weeks after injury. We conclude that acute retrograde axon degeneration is regulated by Akt/Rheb/mTor signaling pathways.
轴突变性是神经退行性疾病的一个标志，包括阿尔茨海默病和帕金森病。这种变性不是一个被动的事件，而是一个由不同于介导细胞体破坏的经典程序性细胞死亡途径的机制介导的主动过程。人们对涉及的不同机制知之甚少，特别是逆行轴突变性的机制。我们之前在黑质纹状体投射的活体动物退化模型中观察到，激酶的组成激活形式，豆蔻酰化 Akt（Myr-Akt），表现出抑制程序性细胞死亡和保留多巴胺神经元细胞体的能力。在这里，我们在神经毒素和物理损伤（轴突切断）模型中都表明，Myr-Akt 还能够通过抑制急性逆行轴突变性来保留多巴胺能轴突。这种细胞表型与哺乳动物雷帕霉素靶蛋白（mTor）活性的增加有关，并且可以通过 mTor 的上游激活剂小 GTPase Rheb 的组成激活形式来重现。在这些模型中，轴突变性伴随着巨自噬的发生，Myr-Akt 抑制了巨自噬。在成年小鼠中条件性缺失必需的自噬调节剂 Atg7 也能在这些急性逆行变性模型中实现显著的轴突保护。Myr-Akt 和 Atg7 缺失提供的保护是强大而持久的，因为在损伤后数周仍能观察到对轴突和多巴胺纹状体支配的保护。我们得出结论，急性逆行轴突变性受 Akt/Rheb/mTor 信号通路调节。
