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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.

SUBMITTER: Kumar V

PROVIDER: S-EPMC4570211 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Molecular Mechanism of Switching of TrkA/p75(NTR) Signaling in Monocrotophos Induced Neurotoxicity.

Kumar Vivek V Gupta Amit Kumar AK Shukla Rajendra Kumar RK Tripathi Vinay Kumar VK Jahan Sadaf S Pandey Ankita A Srivastava Akriti A Agrawal Megha M Yadav Sanjay S Khanna Vinay Kumar VK Pant Aditya Bhushan AB

Scientific reports 20150915

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 ce ...[more]

PMID: 26370177

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Project description:Environmental tobacco smoke remains a major risk factor, for both smokers and non-smokers, able to trigger the initiation and/or the progression of several human diseases. Although in recent times governments have acted with the aim of banning or strongly reducing its impact within public places and common spaces, environmental tobacco smoke remains a major pollutant in private places, such as the home environment or cars. Several inflammatory and long-term biomarkers have been analysed and well-described, but the list of mediators modulated during the early phases of inhalation of environmental tobacco smoke needs to be expanded. The aim of this study was to measure the short-term effects after exposure to side-stream smoke on Nerve Growth Factor and its receptors Tropomyosin-related kinase A and neurotrophin p75, molecules already described in health conditions and respiratory diseases. Twenty-one non-smokers were exposed to a home-standardized level of SS as well as to control smoke-free air. Nerve Growth Factor and inflammatory cytokines levels, as well the expression of Tropomyosin-related kinase A and neurotrophin receptor p75, were analysed in white blood cells. The present study demonstrates that during early phases, side-stream smoke exposure induced increases in the percentage of neurotrophin receptor p75-positive white blood cells, in their mean fluorescent intensity, and in gene expression. In addition, we found a positive correlation between the urine cotinine level and the percentage of neurotrophin receptor-positive white blood cells. For the first time, the evidence that short-term exposure to side-stream smoke is able to increase neurotrophin receptor p75 expression confirms the very early involvement of this receptor, not only among active smokers but also among non-smokers exposed to SS. Furthermore, the correlation between cotinine levels in urine and the increase in neurotrophin receptor p75-positive white blood cells could represent a potential novel molecule to be investigated for the detection of SS exposure at early time points.

Dataset Information

Molecular Mechanism of Switching of TrkA/p75(NTR) Signaling in Monocrotophos Induced Neurotoxicity.

Publications

Molecular Mechanism of Switching of TrkA/p75(NTR) Signaling in Monocrotophos Induced Neurotoxicity.

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