System Level Modeling and Analysis of TNF-a mediated Sphingomyelin Signaling Pathway in Neurological Disorders for the Prediction of Therapeutic Targets

Abstract

Sphingomyelin (SM) belongs to a class of lipids termed as sphingolipids. It is an important component of cell membranes that is present in the myelin sheath of nerve cell axons in high concentrations. TNF-a is a potent pro-inflammatory cytokine as well as the master regulator of sphingomyelin signaling pathway, that is generated in response to various neurological disorders like Alzheimer’s disease, Parkinson’s disease and Multiple Sclerosis. As second messenger, sphingomyelin and its downstream sphingolipids are capable of activating various signaling cascades like PI3K/AKT and MAPK/ERK pathways and control diverse processes coupled with neuronal viability, survival and death. The current study offers a comprehensive insilico systems analysis of TNF-a mediated sphingomyelin and related signaling cascades using model-based quantitative approach. Computational modeling of the inflammation enabled to study the system dynamics of neuronal cell injury. Network and sensitivity analysis of the model unveiled the importance of essential reaction parameters and components during advanced stages of neuroinflammation. Moreover, the efficacy and potency of FDA-approved drugs at later stages of neuronal inflammation was also evaluated by studying model’s response towards inhibition of respective proteins/enzymes. The repurposing of the drugs, namely, Etanercept and Scyphostatin was found impracticable during inflammatory conditions. However, Nivocasan effectively reduced neuronal apoptosis via its inhibitory mechanism on the caspases.