PDF(Pubmed)
Abstract：
Introduction: Kinesin family member 5A (KIF5A) is a motor neuron protein expressed in neurons and involved in anterograde transportation of organelles, proteins, and RNA. Variations in the KIF5A gene that interfere with axonal transport have emerged as a distinguishing feature in several neurodegenerative disorders, including hereditary spastic paraplegia (HSP10), Charcot-Marie-Tooth disease type 2 (CMT2), and Amyotrophic Lateral Sclerosis (ALS). Methods: In this study, we implemented a computational structural and systems biology approach to uncover the role of KIF5A in ALS. Using the computational structural biology method, we explored the role of non-synonymous Single Nucleotide Polymorphism (nsSNPs) in KIF5A. Further, to identify the potential inhibitory molecule against the highly destabilizing structure variant, we docked 24 plant-derived phytochemicals involved in ALS. Results: We found KIF5AS291F variant showed the most structure destabilizing behavior and the phytocompound \"epigallocatechin gallate\" showed the highest binding affinity (-9.0 Kcal/mol) as compared to wild KIF5A (-8.4 Kcal/mol). Further, with the systems biology approach, we constructed the KIF5A protein-protein interaction (PPI) network to identify the associated Kinesin Families (KIFs) proteins, modules, and their function. We also constructed a transcriptional and post-transcriptional regulatory network of KIF5A. With the network topological parameters of PPIN (Degree, Bottleneck, Closeness, and MNC) using CytoHubba and computational knock-out experiment using Network Analyzer, we found KIF1A, 5B, and 5C were the significant proteins. The functional modules were highly enriched with microtubule motor activity, chemical synaptic transmission in neurons, GTP binding, and GABA receptor activity. In regulatory network analysis, we found KIF5A post-transcriptionally down-regulated by miR-107 which is further transcriptionally up-regulated by four TFs (HIF1A, PPARA, SREBF1, and TP53) and down-regulated by three TFs (ZEB1, ZEB2, and LIN28A). Discussion: We concluded our study by finding a crucial variant of KIF5A and its potential therapeutic target (epigallocatechin gallate) and KIF5A associated significant genes with important regulators which could decrypt the novel therapeutics in ALS and other neurodegenerative diseases.
摘要：
简介：驱动蛋白家族成员5A（KIF5A）是一种在神经元中表达的运动神经元蛋白，参与细胞器的顺行运输。蛋白质，RNA。干扰轴突运输的KIF5A基因变异已成为几种神经退行性疾病的一个显著特征。包括遗传性痉挛性截瘫（HSP10），Charcot-Marie-Tooth病2型(CMT2),肌萎缩侧索硬化症（ALS）。方法:在本研究中,我们实施了一种计算结构和系统生物学方法来揭示KIF5A在ALS中的作用.使用计算结构生物学方法，我们探索了非同义单核苷酸多态性（nsSNP）在KIF5A中的作用。Further,为了鉴定针对高度不稳定结构变体的潜在抑制分子，我们对接了24种与ALS有关的植物来源的植物化学物质。结果：我们发现KIF5AS291F变体显示出最多的结构不稳定行为，与野生KIF5A（-8.4Kcal/mol）相比，植物化合物“表没食子儿茶素没食子酸酯”显示出最高的结合亲和力（-9.0Kcal/mol）。Further,用系统生物学方法，我们构建了KIF5A蛋白-蛋白相互作用（PPI）网络来鉴定相关驱动蛋白家族（KIFs）蛋白，模块，和他们的功能。我们还构建了KIF5A的转录和转录后调控网络。用PPIN(度，瓶颈,亲近,和MNC)使用CytoHubba和使用网络分析仪的计算敲除实验，我们发现了KIF1A,5B,5C是重要的蛋白质。功能模块高度丰富了微管运动活动，神经元中的化学突触传递，GTP结合，和GABA受体活性。在监管网络分析中，我们发现KIF5A在转录后被miR-107下调，而miR-107在转录后被4种TF（HIF1A，PPARA,SREBF1和TP53）并被三种TF（ZEB1，ZEB2和LIN28A）下调。讨论：我们通过发现KIF5A的关键变体及其潜在的治疗靶标（表没食子儿茶素没食子酸酯）和KIF5A与重要调节因子相关的重要基因，可以解密ALS和其他神经退行性疾病的新疗法，从而结束了我们的研究。
