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.

This paper presents the first report of amyotrophic lateral sclerosis (ALS) kindred due to the KIF5A p.Arg1007Lys, a splice-altering variant.
An index case was a 54-year-old male who developed progressive gait difficulty and imbalance followed by mild parkinsonism, spasticity, neuropathy, ataxia, and cognitive impairment with predominant subcortical frontal involvement. Brain MRI showed marked bilateral parietal lobes atrophy. Electromyography demonstrated chronic diffuse neurogenic changes. Due to the positive history of similar symptoms in his father and the diagnosis of ALS in 10 other family members, extensive genetic testing was pursued.
Genetic screening for GRN, C9orf72, TARDBP, SOD1, FUS, MAPT mutations, and hereditary ataxia panel, was unremarkable. Whole-exome sequencing revealed c.3020G > A (p.Arg1007Lys) mutation in the KIF5A gene, later confirmed in two affected relatives.
Similar to previous reports on KIF5A-related ALS, our index case, had a mild disease course with prolonged survival. However, as the rate of progression and survival time differed even among the same family members, other factors were probably at play. Additionally, our index case and his father displayed features overlapping ALS, spastic paraplegia, Charcot-Marie-Tooth disease type 2, and frontotemporal dementia. Therefore, we suggest considering KIF5A mutations in the differential diagnosis, particularly in the presence of overlapping features of spasticity, neuropathy, cerebellar ataxia, and dementia.

Glioma is emerging as an aggressive type of glioma characterized by invasive growth pattern and dismal oncologic outcomes. microRNAs (miRNAs) have been attracting research attention in tumorigenesis. Herein, the aim of the current investigation was to explore the functional role of mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) containing miR-503 in glioma. The glioma tissues and corresponding normal brain tissues were collected from patients with glioma, followed by quantification of miR-503, kinesin family member 5A (KIF5A) and interleukin-7 (IL-7). EVs were isolated from bone marrow MSCs and identified by transmission electron microscope and nanoparticle tracking analysis. EVs from miR-503 mimic-transfected MSCs, miR-503 agomir,, oe-KIF5A, or sh-IL-7 was delivered into glioma cells to determine their effects on biological behaviors of glioma and T cells as well as the release of immunosuppressive factors. Lastly, a mouse model of glioma was developed to validate the function in vivo. miR-503 was expressed at a high level in glioma tissues while KIF5A was poorly expressed and targeted by miR-503. Furthermore, miR-503 loaded in MSC-EVs or upregulated miR-503 was demonstrated to facilitate glioma cell proliferation, migration and invasion accompanied by promoted release of immunosuppressive factors. Effects of overexpressed KIF5A on T cell behavior modulation were dependent on the IL-7 signaling pathway. Such results were reproduced in mice with glioma. Collectively, the discovery of miR-503 incorporated in MSC-EVs being a regulator that controls immune escape in glioma provides a novel molecular insight that holds promises to develop therapeutic strategies against glioma.

MicroRNAs (miRNAs) are small non-coding RNAs that participate in various biological and cellular processes by regulating target gene expression. miRNAs are also known to play vital roles in the pathogenesis of various diseases, including infections, as well as the disease progression and defense responses. In this study, we examined the expression levels of pol-miR-140-3p and its target gene, kinesin family member 5A (KIF5A), in association with the Streptococcus parauberis (S. parauberis) infection, a major bacterial pathogen that causes streptococcosis in olive flounder (Paralichthys olivaceus). KIF5A is a heavy chain isoform of kinesin-1, which is known to be brain-specific, and this study is the first examination of KIF5A expression related to the regulation of miRNA in olive flounder (named PoKIF5A). There were significant differences in expression levels between infected and healthy olive flounder as the expression of pol-miR-140-3p in the infected fish was lower than that in the control, while the expression of PoKIF5A was higher in the infected fish than in the healthy controls. These contradictory results suggest that downregulated pol-miR-140-3p induces the expression of PoKIF5A against S. parauberis infection in olive flounder.