AUTHOR=Kumar Rupesh , Madhavan Thirumurthy , Ponnusamy Kalaiarasan , Sohn Honglae , Haider Shazia 

TITLE=Computational study of the motor neuron protein KIF5A to identify nsSNPs, bioactive compounds, and its key regulators

JOURNAL=Frontiers in Genetics

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2023.1282234

DOI=10.3389/fgene.2023.1282234

ISSN=1664-8021

ABSTRACT=<p><bold>Introduction:</bold> Kinesin family member 5A (<italic>KIF5A</italic>) 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).</p><p><bold>Methods:</bold> 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 <italic>KIF5A</italic>. Further, to identify the potential inhibitory molecule against the highly destabilizing structure variant, we docked 24 plant-derived phytochemicals involved in ALS.</p><p><bold>Results:</bold> We found KIF5A<sup>S291F</sup> 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 <italic>KIF5A</italic> (−8.4 Kcal/mol). Further, with the systems biology approach, we constructed the <italic>KIF5A</italic> 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 <italic>KIF5A</italic>. 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 <italic>KIF5A</italic> 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).</p><p><bold>Discussion:</bold> We concluded our study by finding a crucial variant of KIF5A and its potential therapeutic target (epigallocatechin gallate) and <italic>KIF5A</italic> associated significant genes with important regulators which could decrypt the novel therapeutics in ALS and other neurodegenerative diseases.</p>