Ingenuity pathway analysis of α-synuclein predicts potential signaling pathways, network molecules, biological functions, and its role in neurological diseases

Despite the knowledge that mutation, multiplication, and anomalous function of alpha-synuclein cause progressive transformation of alpha-synuclein monomers into toxic amyloid fibrils in neurodegenerative diseases, the understanding of canonical signaling, interaction network molecules, biological functions, and role of alpha-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 alpha-synuclein. IPA of the alpha-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 alpha-synuclein. A frequency distribution analysis of alpha-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 alpha-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 alpha-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 alpha-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 alpha-synuclein signaling cascades. Taken together, the first IPA analysis of alpha-synuclein predicted PD as the key toxicity pathway, neurodegeneration as the major pathological outcome, and inflammatory mediators as the critical interacting partners of alpha-synuclein.

Automated summary

Despite the ambiguous understanding of the canonical signaling, interaction network molecules, biological functions, and role of alpha-synuclein, the use of artificial intelligence and Bioinformatics tools like ingenuity pathway analysis (IPA) have allowed us to analyze and predict the key pathways and interactions of alpha-synuclein. The study reveals neuroinflammation, Huntington's disease, and sirtuin signaling as the important pathways, and predicts Parkinson's disease as the key toxicity pathway of alpha-synuclein.