In Frontiers in molecular neuroscience
Despite the knowledge that mutation, multiplication, and anomalous function of α-synuclein cause progressive transformation of α-synuclein monomers into toxic amyloid fibrils in neurodegenerative diseases, the understanding of canonical signaling, interaction network molecules, biological functions, and role of α-synuclein remains ambiguous. The evolution of artificial intelligence and Bioinformatics tools have enabled us to analyze a vast pool of data to draw meaningful conclusions about the events occurring in complex biological systems. We have taken the advantage of such a Bioinformatics tool, ingenuity pathway analysis (IPA) to decipher the signaling pathways, interactome, biological functions, and role of α-synuclein. IPA of the α-synuclein NCBI gene dataset revealed neuroinflammation, Huntington's disease, TREM1, phagosome maturation, and sirtuin signaling as the key canonical signaling pathways. IPA further revealed Parkinson's disease (PD), sumoylation, and SNARE signaling pathways specific to the toxicity of α-synuclein. A frequency distribution analysis of α-synuclein-associated genes from the NCBI dataset that appeared in the predicted canonical pathways revealed that NFKB1 was the most populated gene across the predicted pathways followed by FOS, PRKCD, TNF, GSK3B, CDC42, IL6, MTOR, PLCB1, and IL1B. Overlapping of the predicted top-five canonical signaling pathways and the α-synuclein NCBI gene dataset divulged that neuroinflammation signaling was the most overlapped pathway, while NFKB1, TNF, and CASP1 were the most shared molecules among the pathways. The major diseases associated with α-synuclein were predicted to be neurological diseases, organismal injury and abnormalities, skeletal and muscular disorders, psychological disorders, and hereditary disorders. The molecule activity predictor (MAP) analysis of the principal interaction network of α-synuclein gene SNCA revealed that SNCA directly interacts with APP, CLU, and NEDD4, whereas it indirectly communicates with CALCA and SOD1. Besides, IPA also predicted amyloid plaque forming APP, cytokines/inflammatory mediators IL1B, TNF, MIF, PTGS2, TP53, and CCL2, and kinases of MAPK family Mek, ERK, and P38 MAPK as the top upstream regulators of α-synuclein signaling cascades. Taken together, the first IPA analysis of α-synuclein predicted PD as the key toxicity pathway, neurodegeneration as the major pathological outcome, and inflammatory mediators as the critical interacting partners of α-synuclein.
Suthar Sharad Kumar, Lee Sang-Yoon
2022
biological functions and diseases, canonical signaling pathways, ingenuity pathway analysis, interactome, neuroinflammation, regulators, toxicity, α-synuclein
