Dysfunction of Membrane Trafficking Leads to Ischemia-Reperfusion Injury After Transient Cerebral Ischemia.
Dysfunction of Membrane Trafficking Leads to Ischemia-Reperfusion Injury After Transient Cerebral Ischemia.
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DOI：
10.1007/s12975-017-0572-0
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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;Hu B
由于轴突末端和树突分支丰富，神经元需要极高水平的膜运输活动。因此，膜运输通路的缺陷是大多数（甚至可能是所有）神经退行性疾病的一个特征。细胞内主要的膜运输通路之一是高尔基体（以下简称高尔基体）—晚期内体—溶酶体轴，用于供应溶酶体酶。该通路受N - 乙基马来酰亚胺敏感因子（NSF）ATP酶的调控。这篇综述文章旨在探讨一个新假设，即脑缺血会使NSF ATP酶失活，从而在缺血后阶段引发一系列事件，包括高尔基体—内体—溶酶体通路的破坏、组织蛋白酶B（CTSB）的释放以及线粒体外膜通透性增加（MOMP）的诱导。最近的研究支持了这一假设，这些研究表明，在脑缺血后注定死亡的神经元中，NSF被困在无活性的蛋白质聚集体中。结果，高尔基体、运输小泡（TVs）和晚期内体（LEs）积累并受损，随后CTSB从这些受损结构中释放出来。适度释放的CTSB会切割Bax样BH3蛋白（Bid），使其成为有活性的截短型Bid（tBid）。有活性的tBid随后转移到线粒体外膜，导致BCL2相关X蛋白（Bax）寡聚化，形成线粒体外膜孔，并释放线粒体膜间蛋白。然而，大量CTSB的释放会不加选择地消化细胞内蛋白质，从而诱导细胞死亡。基于这些新发现，我们提出一个新假设，即脑缺血导致NSF失活，进而导致受损的高尔基体、TVs和LEs大量积累，CTSB致命性释放，MOMP被诱导，最终导致脑缺血 - 再灌注损伤。
Neurons requires an extraordinarily high level of membrane trafficking activities because of enriched axonal terminals and dendritic branches. For that reason, defects in the membrane trafficking pathway are a hallmark of most, and may be all, neurodegenerative disorders. A major cellular membrane trafficking pathway is the Golgi apparatus (Golgi hereafter) – late endosome - lysosome axis for supplying lysosomal enzymes. This pathway is regulated by N-ethylmaleimide sensitive factor (NSF) ATPase. This review article is to discuss a novel hypothesis that brain ischemia inactivates NSF ATPase, resulting in a cascade of events of disruption of the Golgi – endosome - lysosome pathway, release of cathepsin B (CTSB), and induction of mitochondrial outer membrane permeabilization (MOMP) during the postischemic phase. This hypothesis is supported by recent studies demonstrating that NSF is trapped into inactive protein aggregates in neurons destined to die after brain ischemia. Consequently, Golgi, transport vesicles (TVs), and late endosomes (LEs) are accumulated and damaged, which is followed by CTSB release from these damaged structures. Moderate release of CTSB cleaves Bax-like BH3 protein (Bid) to become active truncated Bid (tBid). Active tBid is then translocated to the mitochondrial outer membrane, resulting in oligomerization of BCL2 Associated X Protein (Bax) forming the mitochondrial outer membrane pores, and releasing mitochondrial intramembranous proteins. Extensive CTSB release, however, can digest cellular proteins indiscriminately to induce cell death. Based on these new observations, we propose a novel hypothesis, i.e., brain ischemia leads to NSF inactivation, resulting in a massive buildup of damaged Golgi, TVs and LEs, fatal release of CTSB, induction of MOMP, and eventually brain ischemia-reperfusion injury.
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