Impaired autophagy in neurons after disinhibition of mammalian target of rapamycin and its contribution to epileptogenesis.
Impaired autophagy in neurons after disinhibition of mammalian target of rapamycin and its contribution to epileptogenesis.
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DOI：
10.1523/jneurosci.2392-12.2012
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发表时间：
2012-11-07
期刊：
影响因子：
--
通讯作者：
Huang Y
中科院分区：
文献类型：
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作者：
McMahon J;Huang X;Yang J;Komatsu M;Yue Z;Qian J;Zhu X;Huang Y
哺乳动物雷帕霉素靶标(MTOR)通路的某些突变，尤其是那些影响结节性硬化症复合体(TSC)的突变，会导致mTOR的异常激活，导致人类和动物模型癫痫的高发病率。虽然mTOR的过度激活与癫痫的发生密切相关，相反，在几种模型中，雷帕霉素抑制mTOR对癫痫发作具有保护作用，但下游的癫痫机制仍不清楚。自噬是一种分解代谢过程，通过调节细胞质成分的周转在细胞动态平衡中发挥重要作用，受到mTOR的负调控。在这里，我们证明了自噬在前脑特异性条件性TSC1和磷酸酶和紧张素同源基因敲除(KO)小鼠的脑组织中受到抑制，这两种小鼠都表现出异常的mTOR激活和癫痫发作。此外，我们还发现自噬在人类TSC患者的大脑中被抑制。此外，在小鼠前脑神经元中有条件地删除ATG7，这是自噬的基本调节因子，足以促进自发性癫痫的发展。因此，我们的研究表明，自噬受损有助于癫痫的发生，这可能是癫痫治疗和/或预防的潜在治疗靶点。
Certain mutations within the mammalian target of rapamycin (mTOR) pathway, most notably those affecting the tuberous sclerosis complex (TSC), lead to aberrant activation of mTOR and result in a high incidence of epilepsy in humans and animal models. Although hyperactivation of mTOR has been strongly linked to the development of epilepsy and, conversely, inhibition of mTOR by rapamycin treatment is protective against seizures in several models, the downstream epileptic mechanisms have remained elusive. Autophagy, a catabolic process which plays a vital role in cellular homeostasis by mediating the turnover of cytoplasmic constituents, is negatively regulated by mTOR. Here we demonstrate that autophagy is suppressed in brain tissues of forebrain-specific conditional TSC1 and phosphatase and tensin homlog (PTEN) knockout (KO) mice, both of which display aberrant mTOR activation and seizures. In addition, we also discovered that autophagy is suppressed in the brains of human TSC patients. Moreover, conditional deletion of Atg7, an essential regulator of autophagy, in mouse forebrain neurons is sufficient to promote development of spontaneous seizures. Thus, our study suggests that impaired autophagy contributes to epileptogenesis, which may be of interest as a potential therapeutic target for epilepsy treatment and/or prevention.