Zhang Hongfeng, Huang Timothy, Hong Yujuan, Yang Weijie, Zhang Xian, Luo Hong, Xu Huaxi, Wang Xin
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Collaborative Innovation Center for Brain Science, Xiamen University, Xiamen, China.
Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, San Diego, CA, United States.
Front Aging Neurosci. 2018 Mar 26;10:79. doi: 10.3389/fnagi.2018.00079. eCollection 2018.
The retromer complex and associated sorting nexins (SNXs) comprise a critical trafficking machinery which mediates endosomal protein sorting. Retromer and/or SNX dysfunction has been linked to several neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and Down's syndrome (DS). In AD, deficiency of the retromer complex or its cargo proteins impairs endosomal trafficking of amyloid precursor protein (APP), resulting in the overproduction of β-amyloid (Aβ). Several SNX components directly interact with APP or APP-cleaving enzymes (β- and γ-secretases) to regulate amyloidogenic APP processing and Aβ generation. In addition, PD-linked mutations in retromer components cause mistrafficking of retromer cargo proteins and mitochondrial dysfunction, and dysregulation retromer-mediated trafficking has been considered as an important cause of hereditary spastic paraplegia (HSP) and neuronal ceroid lipofuscinoses (NCLs). Moreover, SNX27 deficiency is an important contributor for synaptic and cognitive impairment in DS. Here we review recent findings describing the retromer complex and/or SNXs-mediated endosomal sorting in neurodegenerative disorders.
回收蛋白复合物及相关分选连接蛋白（SNXs）构成了一种关键的转运机制，介导内体蛋白分选。回收蛋白和/或SNX功能障碍与包括阿尔茨海默病（AD）、帕金森病（PD）和唐氏综合征（DS）在内的多种神经退行性疾病有关。在AD中，回收蛋白复合物或其货物蛋白的缺乏会损害淀粉样前体蛋白（APP）的内体转运，导致β-淀粉样蛋白（Aβ）产生过多。几种SNX成分直接与APP或APP切割酶（β-和γ-分泌酶）相互作用，以调节淀粉样蛋白生成性APP加工和Aβ生成。此外，回收蛋白成分中与PD相关的突变会导致回收蛋白货物蛋白的错误转运和线粒体功能障碍，回收蛋白介导的转运失调被认为是遗传性痉挛性截瘫（HSP）和神经元蜡样脂褐质沉积症（NCLs）的重要原因。此外，SNX27缺乏是DS中突触和认知障碍的重要因素。在此，我们综述了描述回收蛋白复合物和/或SNXs介导的神经退行性疾病内体分选的最新研究发现。
