Molecular mechanism of switching of TrkA/p75 NTR signaling in monocrotophos induced neurotoxicity

Abstract

We demonstrate the role of molecular switching of TrkA/p75 NTR signaling cascade in organophosphate pesticide-Monocrotophos (MCP) induced neurotoxicity in stem cell derived cholinergic neurons and in rat brain. Our in-silico studies reveal that MCP followed the similar pattern of binding as staurosporine and AG-879 (known inhibitors of TrkA) with TrkA protein (PDB ID: 4AOJ) at the ATP binding sites. This binding of MCP to TrkA led to the conformational change in this protein and triggers the cell death cascades. The in-silico findings are validated by observing the down regulated levels of phosphorylated TrkA and its downstream molecules viz., pERK1/2, pAkt and pCREB in MCP-exposed cells. We observe that these MCP induced alterations in pTrkA and downstream signaling molecules are found to be associated with apoptosis and injury to neurons. The down-regulation of TrkA could be linked to increased p75 NTR. The in-vitro studies could be correlated in the rat model. The switching of TrkA/p75 NTR signaling plays a central role in MCP-induced neural injury in rBNSCs and behavioral changes in exposed rats. Our studies significantly advance the understanding of the switching of TrkA/p75 NTR that may pave the way for the application of TrkA inducer/p75 NTR inhibitor for potential therapeutic intervention in various neurodegenerative disorders.