Department of Anesthesiology and Neurology, Shock Trauma and Anesthesiology Research Center, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
Veterans Affairs Maryland Health Center System, 10 North Greene Street, Baltimore, MD, 21201, USA.
Transl Stroke Res. 2018 Jun;9(3):215-222. doi: 10.1007/s12975-017-0572-0. Epub 2017 Oct 11.
Neurons require 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.
神经元由于富含轴突末梢和树突分支，因此需要极高水平的膜运输活动。出于这个原因，膜运输途径的缺陷是大多数（如果不是全部的话）神经退行性疾病的标志。一个主要的细胞内膜运输途径是高尔基体（以下简称高尔基体）-晚期内体-溶酶体轴，用于供应溶酶体酶。该途径受 N-乙基马来酰亚胺敏感因子（NSF）ATP 酶调节。本文综述讨论了一个新假说，即脑缺血使 NSF ATP 酶失活，导致一系列事件的级联反应，破坏高尔基体-内体-溶酶体途径，组织蛋白酶 B（CTSB）释放，以及诱导线粒体膜通透性（MOMP）在缺血后阶段。这个假说得到了最近的研究支持，这些研究表明 NSF 在脑缺血后注定死亡的神经元中被捕获到无活性的蛋白质聚集体中。因此，高尔基体、运输小泡（TVs）和晚期内体（LEs）被积累和损伤，随后这些受损结构中的 CTSB 释放。中度释放的 CTSB 可将 Bax 样 BH3 蛋白（Bid）切割成活性截断 Bid（tBid）。活性 tBid 然后被转运到线粒体外膜，导致 BCL2 相关 X 蛋白（Bax）寡聚形成线粒体外膜孔，并释放线粒体内膜蛋白。然而，大量的 CTSB 释放可以不加区别地消化细胞蛋白，导致细胞死亡。基于这些新的观察结果，我们提出了一个新的假说，即脑缺血导致 NSF 失活，导致大量受损的高尔基体、TVs 和 LEs 的堆积，致命的 CTSB 释放，MOMP 的诱导，最终导致脑缺血再灌注损伤。
