Inhibition of autophagy prevents hippocampal pyramidal neuron death after hypoxic-ischemic injury
Inhibition of autophagy prevents hippocampal pyramidal neuron death after hypoxic-ischemic injury
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DOI：
10.2353/ajpath.2008.070876
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发表时间：
2008-02-01
影响因子：
6
通讯作者：
Uchiyama, Yasuo
中科院分区：
文献类型：
--
作者：
Koike, Masato;Shibata, Masahiro;Uchiyama, Yasuo
新生儿缺氧/缺血（H/I）脑损伤导致神经功能障碍，包括认知和运动功能障碍以及癫痫发作。然而，调节H/I损伤后神经元死亡的分子机制尚不清楚，仍存在争议。在这里，我们表明，Atg7，自噬诱导所必需的基因，是H/I诱导的神经元死亡的关键介质。H/I损伤的新生小鼠表现出显著增加的自噬体形成和广泛的海马神经元死亡，这是由caspase-3依赖性和非依赖性执行调节的。缺乏Atg7的小鼠表现出几乎完全的保护H/I诱导的半胱天冬酶-3活化和神经元死亡，表明Atg7关键地位于多个神经元死亡执行者途径的上游。成人H/I脑损伤也产生自噬的显着增加，但与新生儿H/I不同，神经元死亡几乎完全是半胱天冬酶-3-独立的。这些数据表明，自噬在H/I损伤后触发神经元死亡执行中起着至关重要的作用，Atg 7代表了一个有吸引力的治疗靶点，用于最大限度地减少与H/I脑损伤相关的神经功能缺损。
Neonatal hypoxic/ischemic (H/I) brain injury causes neurological impairment, including cognitive and motor dysfunction as well as seizures. However, the molecular mechanisms regulating neuron death after H/I injury are poorly defined and remain controversial. Here we show that Atg7, a gene essential for autophagy induction, is a critical mediator of H/I-induced neuron death. Neonatal mice subjected to H/I injury show dramatically increased autophagosome formation and extensive hippocampal neuron death that is regulated by both caspase-3-dependent and -independent execution. Mice deficient in Atg7 show nearly complete protection from both H/I-induced caspase-3 activation and neuron death indicating that Atg7 is critically positioned upstream of multiple neuronal death executioner pathways. Adult H/I brain injury also produces a significant increase in autophagy, but unlike neonatal H/I, neuron death is almost exclusively caspase-3-independent. These data suggest that autophagy plays an essential role in triggering neuronal death execution after H/I injury and Atg7 represents an attractive therapeutic target for minimizing the neurological deficits associated with H/I brain injury.