Akt suppresses retrograde degeneration of dopaminergic axons by inhibition of macroautophagy.
Akt suppresses retrograde degeneration of dopaminergic axons by inhibition of macroautophagy.
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DOI：
10.1523/jneurosci.5519-10.2011
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发表时间：
2011-02-09
期刊：
影响因子：
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通讯作者：
Burke RE
中科院分区：
文献类型：
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作者：
Cheng HC;Kim SR;Oo TF;Kareva T;Yarygina O;Rzhetskaya M;Wang C;During M;Talloczy Z;Tanaka K;Komatsu M;Kobayashi K;Okano H;Kholodilov N;Burke RE
轴突变性是神经退行性疾病的标志，包括阿尔茨海默病和帕金森病。这种退化不是被动事件，而是主动过程，由与介导细胞索马破坏的程序性细胞死亡的经典途径不同的机制介导。很少有人知道的各种机制，特别是逆行轴突变性。我们以前在黑质-纹状体投射退化的活体动物模型中观察到，激酶Akt（Myr-Akt）的组成性活性形式表现出抑制程序性细胞死亡和保护多巴胺神经元的索马的能力。在这里，我们表明在神经毒素和物理损伤（轴突切断术）模型中，Myr-Akt也能够由于抑制急性逆行轴突变性而保留它们的轴突。这种细胞表型与mTor活性增加相关，并且可以通过小GTdR heb（mTor的上游激活剂）的组成型活性形式重现。这些模型中的轴突变性伴随着巨自噬的发生，巨自噬被Myr-Akt抑制。在成年小鼠中有条件地删除必需的自噬介质Atg 7也在这些急性退行性变性模型中实现了显著的轴突保护。Myr-Akt和Atg 7缺失两者提供的保护是稳健和持久的，因为在损伤后数周仍观察到其作为轴突和多巴胺能纹状体神经支配两者的保护。我们的结论是，急性逆行性轴突变性是由Akt/Rheb/mTor信号通路调节。
Axon degeneration is a hallmark of neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease. Such degeneration is not a passive event, but rather is 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 nigro-striatal projection that a constitutively active form of the kinase 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 their axons due to suppression of acute retrograde axon degeneration. This cellular phenotype is associated with increased 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.