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Molecular Mechanism of Switching of TrkA/p75NTR Signaling in Monocrotophos Induced Neurotoxicity.
- Source :
-
Scientific Reports . 9/18/2015, p14038. 1p. - Publication Year :
- 2015
-
Abstract
- We demonstrate the role of molecular switching of TrkA/p75NTR 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 p75NTR. The in-vitro studies could be correlated in the rat model. The switching of TrkA/p75NTR 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/p75NTR that may pave the way for the application of TrkA inducer/p75NTR inhibitor for potential therapeutic intervention in various neurodegenerative disorders. [ABSTRACT FROM AUTHOR]
- Subjects :
- *MONOCROTOPHOS
*NEUROTOXICOLOGY
*NEURONS
*APOPTOSIS
*PHOSPHORYLATION
*CELL death
Subjects
Details
- Language :
- English
- ISSN :
- 20452322
- Database :
- Academic Search Index
- Journal :
- Scientific Reports
- Publication Type :
- Academic Journal
- Accession number :
- 109534402
- Full Text :
- https://doi.org/10.1038/srep14038