Molecular Mechanism of Switching of TrkA/p75NTR 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...

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Published inScientific reports Vol. 5; no. 1; p. 14038
Main Authors Kumar, Vivek, Gupta, Amit Kumar, Shukla, Rajendra Kumar, Tripathi, Vinay Kumar, Jahan, Sadaf, Pandey, Ankita, Srivastava, Akriti, Agrawal, Megha, Yadav, Sanjay, Khanna, Vinay Kumar, Pant, Aditya Bhushan
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group 15.09.2015
Subjects
Apoptosis
Binding sites
Cell death
Monocrotophos
Neurodegenerative diseases
Neurotoxicity
Organophosphates
Rodents
Staurosporine
Stem cells
TrkA protein
TrkA receptors
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Summary: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep14038