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Nociceptor translational profiling reveals the RagA-mTORC1 network as a critical generator of neuropathic pain

By Salim Megat, Pradipta R Ray, Jamie K. Moy, Tzu-Fang Lou, Paulino Barragan-Iglesias, Yan Li, Grishma Pradhan, Andi Wangzhou, Ayesha Ahmad, Robert Y. North, Patrick M. Dougherty, Arkady Khoutorsky, Nahum Sonenberg, Kevin R. Webster, Gregory Dussor, Zachary T Campbell, Theodore J Price

Posted 02 Jun 2018
bioRxiv DOI: 10.1101/336784

Pain sensing neurons, nociceptors, are key drivers of neuropathic pain. We used translating ribosome affinity purification (TRAP) to comprehensively characterize up- and down-regulated mRNA translation in Scn10a-positive nociceptors in chemotherapy-induced neuropathic pain. We provide evidence that an underlying mechanism driving these changes in gene expression is a sustained mTORC1 activation driven by MNK1-eIF4E signaling. RagA, a GTPase controlling mTORC1 activity, is identified as a novel target of MNK1-eIF4E signaling, demonstrating a new link between these distinct signaling pathways. Neuropathic pain and RagA translation are strongly attenuated by genetic ablation of eIF4E phosphorylation, MNK1 elimination or treatment with the MNK inhibitor eFT508. We reveal a novel translational circuit for the genesis of neuropathic pain with important implications for next generation neuropathic pain therapeutics.

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