Hu Kurt, Gaire Bhakta Prasad, Subedi Lalita, Arya Awadhesh, Teramoto Hironori, Liu Chunli, Hu Bingren
Department of Medicine, Division of Pulmonary and Critical Care, Medical College of Wisconsin, Wisconsin, WI, United States.
Department of Anesthesiology and Neurology, Shock Trauma and Anesthesiology Research Center, University of Maryland School of Medicine, Baltimore, MD, United States.
Front Mol Neurosci. 2021 Sep 28;14:719100. doi: 10.3389/fnmol.2021.719100. eCollection 2021.
A typical neuron consists of a soma, a single axon with numerous nerve terminals, and multiple dendritic trunks with numerous branches. Each of the 100 billion neurons in the brain has on average 7,000 synaptic connections to other neurons. The neuronal endolysosomal compartments for the degradation of axonal and dendritic waste are located in the soma region. That means that all autophagosomal and endosomal cargos from 7,000 synaptic connections must be transported to the soma region for degradation. For that reason, neuronal endolysosomal degradation is an extraordinarily demanding and dynamic event, and thus is highly susceptible to many pathological conditions. Dysfunction in the endolysosomal trafficking pathways occurs in virtually all neurodegenerative diseases. Most lysosomal storage disorders (LSDs) with defects in the endolysosomal system preferentially affect the central nervous system (CNS). Recently, significant progress has been made in understanding the role that the endolysosomal trafficking pathways play after brain ischemia. Brain ischemia damages the membrane fusion machinery co-operated by N-ethylmaleimide sensitive factor (NSF), soluble NSF attachment protein (SNAP), and soluble NSF attachment protein receptors (SNAREs), thus interrupting the membrane-to-membrane fusion between the late endosome and terminal lysosome. This interruption obstructs all incoming traffic. Consequently, both the size and number of endolysosomal structures, autophagosomes, early endosomes, and intra-neuronal protein aggregates are increased extensively in post-ischemic neurons. This cascade of events eventually damages the endolysosomal structures to release hydrolases leading to ischemic brain injury. Gene knockout and selective inhibition of key endolysosomal cathepsins protects the brain from ischemic injury. This review aims to provide an update of the current knowledge, future research directions, and the clinical implications regarding the critical role of the neuronal endolysosomal trafficking pathways in ischemic brain injury.
一个典型的神经元由一个细胞体、一条带有众多神经末梢的单轴突以及多条带有众多分支的树突干组成。大脑中1000亿个神经元中的每一个平均与其他神经元有7000个突触连接。用于降解轴突和树突废物的神经元内溶酶体区室位于细胞体区域。这意味着来自7000个突触连接的所有自噬体和内体货物都必须运输到细胞体区域进行降解。因此，神经元内溶酶体降解是一个极其苛刻且动态的过程，因此极易受到许多病理状况的影响。内溶酶体运输途径的功能障碍几乎出现在所有神经退行性疾病中。大多数在内溶酶体系统存在缺陷的溶酶体贮积症（LSDs）优先影响中枢神经系统（CNS）。最近，在理解脑缺血后内溶酶体运输途径所起的作用方面取得了重大进展。脑缺血会损害由N - 乙基马来酰亚胺敏感因子（NSF）、可溶性NSF附着蛋白（SNAP）和可溶性NSF附着蛋白受体（SNAREs）协同作用的膜融合机制，从而中断晚期内体与终末溶酶体之间的膜到膜融合。这种中断阻碍了所有传入的运输。因此，在缺血后神经元中，内溶酶体结构、自噬体、早期内体和神经元内蛋白质聚集体的大小和数量都大幅增加。这一系列事件最终会损害内溶酶体结构以释放水解酶，导致缺血性脑损伤。基因敲除和对关键内溶酶体组织蛋白酶的选择性抑制可保护大脑免受缺血性损伤。本综述旨在提供关于神经元内溶酶体运输途径在缺血性脑损伤中的关键作用的当前知识、未来研究方向及临床意义的最新信息。
