Inactivation of NSF ATPase Leads to Cathepsin B Release After Transient Cerebral Ischemia.
Inactivation of NSF ATPase Leads to Cathepsin B Release After Transient Cerebral Ischemia.
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DOI：
10.1007/s12975-017-0571-1
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发表时间：
2018-06
影响因子：
6.9
通讯作者：
Hu B
中科院分区：
文献类型：
--
作者：
Yuan D;Liu C;Wu J;Hu B
神经元具有格外大的细胞膜表面积，因此需要极高水平的细胞内膜运输活动。所以，膜运输活动的缺陷会优先影响神经元。控制膜运输活动的一个关键分子是N - 乙基马来酰亚胺敏感因子（NSF）ATP酶。本研究旨在利用双血管闭塞合并低血压（2VO + 低血压）全脑缺血模型，探究NSF ATP酶失活所引发的一系列事件，这些事件会导致短暂性脑缺血后晚期内体（LEs）大量积聚以及组织蛋白酶B（CTSB）的致命性释放。对大鼠进行20分钟的短暂性脑缺血处理，随后分别进行0.5、4、24和72小时的再灌注。分别通过光学显微镜和电子显微镜检查神经元的组织病理学和超微结构。采用蛋白质免疫印迹法和共聚焦显微镜分析高尔基体、内体或溶酶体标志物的水平、重新分布及共定位情况。短暂性脑缺血会导致延迟性神经元死亡，这种死亡主要发生在再灌注48 - 72小时，主要见于海马CA1区以及新皮质（Cx）第3和第5层的锥体神经元。在延迟期内，NSF ATP酶不可逆地被困在注定死亡的缺血后神经元中的无活性蛋白质聚集体内。NSF失活会导致高尔基体片段、转运小泡（TVs）和晚期内体（LEs）大量积聚，以及33千道尔顿晚期内体类型的CTSB释放，继而在短暂性脑缺血后出现延迟性神经元死亡。研究结果支持一个新假设，即短暂性脑缺血会导致NSF失活，从而引发CTSB致命性释放的一系列事件，并导致短暂性脑缺血后的延迟性神经元死亡。
Neurons have extraordinary large cell membrane surface area, thus requiring extremely high levels of intracellular membrane-trafficking activities. Consequently, defects in the membrane-trafficking activities preferentially affect neurons. A critical molecule for controlling the membrane-trafficking activities is the N-ethylmaleimide-sensitive factor (NSF) ATPase. This study is to investigate the cascade of events of NSF ATPase inactivation, resulting in a massive buildup of late endosomes (LEs) and fatal release of cathepsin B (CTSB) after transient cerebral ischemia using the 2-vessel occlusion with hypotension (2VO+Hypotension) global brain ischemia model. Rats were subjected to 20 min of transient cerebral ischemia followed by 0.5, 4, 24, and 72 h of reperfusion. Neuronal histopathology and ultrastructure were examined by the light and electron microscopy, respectively. Western blotting and confocal microscopy were utilized for analyzing the levels, redistribution, and co-localization of Golgi apparatus and endosome or lysosome markers. Transient cerebral ischemia leads to delayed neuronal death that occurs at 48–72 h of reperfusion mainly in hippocampal CA1 and neocortical (Cx) layers 3 and 5 pyramidal neurons. During the delayed period, NSFATPase is irreversibly trapped into inactive protein aggregates selectively in post-ischemic neurons destined to die. NSF inactivation leads to a massive buildup of Golgi fragments, transport vesicles (TVs) and late endosomes (LEs), and release of the 33 kDa LE type of CTSB, which is followed by delayed neuronal death after transient cerebral ischemia. The results support a novel hypothesis that transient cerebral ischemia leads to NSF inactivation, resulting in a cascade of events of fatal release of CTSB and delayed neuronal death after transient cerebral ischemia.
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影响因子：
3.3
作者：
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通讯作者：
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