DEPDC5-dependent mTORC1 signaling mechanisms are critical for the anti-seizure effects of acute fasting.
DEPDC5-dependent mTORC1 signaling mechanisms are critical for the anti-seizure effects of acute fasting.
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DOI：
10.1016/j.celrep.2022.111278
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发表时间：
2022-08-30
期刊：
影响因子：
8.8
通讯作者：
Sahin, Mustafa
中科院分区：
文献类型：
--
作者：
Yuskaitis, Christopher J.;Modasia, Jinita B.;Schrotter, Sandra;Rossitto, Leigh-Ana;Groff, Karenna J.;Morici, Christopher;Mithal, Divakar S.;Chakrabarty, Ram P.;Chandel, Navdeep S.;Manning, Brendan D.;Sahin, Mustafa
众所周知，热量限制和急性禁食可以减少癫痫发作，但具体机制尚不清楚。 mTOR 信号传导被认为是预防禁食癫痫发作的潜在机制。我们证明，小鼠急性禁食后，大脑 mTORC1 信号传导减弱，并且神经元 mTORC1 整合了 GATOR1 复合物介导的氨基酸和结节性硬化症复合物 (TSC) 介导的生长因子信号传导。神经元 mTORC1 对亮氨酸、精氨酸和谷氨酰胺的撤退最为敏感，这些物质依赖于 GATOR1 复合物的一个组成部分 DEPDC5。代谢组学分析表明，Depdc5 神经元特异性敲除小鼠对禁食后大脑氨基酸水平的显着波动具有抵抗力。 Depdc5 神经元特异性基因敲除小鼠对禁食对癫痫发作或癫痫引起的死亡的保护作用具有抵抗力。这些结果证实，急性禁食以 DEPDC5 依赖性方式降低癫痫易感性。调节 GATOR1 和 mTORC1 上游的营养物质可以为癫痫治疗提供合理的治疗策略。尤斯凯蒂斯等人。发现通过 GATOR1 和 mTORC1 的氨基酸感应介导禁食饮食对癫痫发作的保护作用。通过对神经元 mTORC1 信号传导上游调节的深入研究，他们深入了解了大脑中的营养信号传导机制以及这些机制如何介导癫痫发作。
Caloric restriction and acute fasting are known to reduce seizures but through unclear mechanisms. mTOR signaling has been suggested as a potential mechanism for seizure protection from fasting. We demonstrate that brain mTORC1 signaling is reduced after acute fasting of mice and that neuronal mTORC1 integrates GATOR1 complex-mediated amino acid and tuberous sclerosis complex (TSC)-mediated growth factor signaling. Neuronal mTORC1 is most sensitive to withdrawal of leucine, arginine, and glutamine, which are dependent on DEPDC5, a component of the GATOR1 complex. Metabolomic analysis reveals that Depdc5 neuronal-specific knockout mice are resistant to sensing significant fluctuations in brain amino acid levels after fasting. Depdc5 neuronal-specific knockout mice are resistant to the protective effects of fasting on seizures or seizure-induced death. These results establish that acute fasting reduces seizure susceptibility in a DEPDC5-dependent manner. Modulation of nutrients upstream of GATOR1 and mTORC1 could offer a rational therapeutic strategy for epilepsy treatment. Yuskaitis et al. find that amino acid sensing through GATOR1 and mTORC1 mediates the protective effects of dietary fasting on seizures. Through their thorough investigation of the upstream regulation of neuronal mTORC1 signaling, they provide insight into nutrient-signaling mechanisms in the brain and how these mechanisms mediate seizures.
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