Bioinformatic analysis on pathological association of human aminoacyl-tRNA synthetases and their protein network with neurological diseases

Abstract

Aminoacyl-tRNA synthetases (ARSs) are essential enzymes ligating specific amino acids to their cognate tRNA for protein biosynthesis. It is reported that they are also involved in many signaling pathways as crucial mediators. In these multiple activities, they are associated with various human diseases. Many mutations of ARSs have been found to be associated with various neurological diseases. Here, we systematically investigated the statistical association of ARSs and their associated factors such as ARS-interacting multi-functional proteins (AIMPs) with various neurological diseases. A total network of ARSs/AIMPs and their interacting factors was constructed using three protein–protein interaction (PPI) databases. In this network, 586 factors were identified as first-neighbors that are suggested to be directly linked to ARSs/AIMPs and 13,539 factors were identified as second-neighbors that are indirectly linked to ARSs/AIMPs via the first-neighbors. Among the first- and second-neighbors, we selected 1,772 genes associated with 27 neurological diseases (neurological-disease-associated genes

NAGs) from public databases and the literature and identified 86 and 687 factors as the first- and second-neighbor NAGs, respectively. We retrieved 67 gene expression datasets of 24 neurological diseases from Gene Expression Omnibus (GEO) and ArrayExpress. The gene expression profiles of ARSs/AIMPs and their neighboring NAGs were compared with negative controls (non-NAGs). We obtained P values for each dataset and combined them for each disease. Then, the P values for each disease were combined into a value representing the whole set of 24 neurological diseases. Additionally, we created a subnetwork representing biological processes and P values using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). Quite a few ARSs/AIMPs and first- and second-neighbor NAGs were differentially expressed genes (DEGs) in neurodegenerative diseases such as Alzheimers disease and Parkinsons disease. In summary, 20 human cytosolic ARSs and 3 AIMPs are strongly connected to diverse NAGs and are differentially expressed in neurological diseases, indicating their implication in these diseases.