Nociceptor Translational Profiling Reveals the Ragulator-Rag GTPase Complex as a Critical Generator of Neuropathic Pain

dc.contributor.ORCID0000-0003-4281-3985 (Pradhan, G)
dc.contributor.ORCID0000-0002-0628-824X (Burton, MD)
dc.contributor.ORCID0000-0002-3768-6996 (Campbell, ZT)
dc.contributor.ORCID0000-0002-6971-6221 (Price, TJ)
dc.contributor.authorMegat, Salim
dc.contributor.authorRay, Pradipta R.
dc.contributor.authorMoy, Jamie K.
dc.contributor.authorLou, Tzu-Fang
dc.contributor.authorBarragan-Iglesias, Paulino
dc.contributor.authorLi, Yan
dc.contributor.authorPradhan, Grishma
dc.contributor.authorWanghzou, Andi
dc.contributor.authorAhmad, Ayesha
dc.contributor.authorBurton, Michael D.
dc.contributor.authorNorth, Robert Y.
dc.contributor.authorDougherty, Patrick M.
dc.contributor.authorKhoutorsky, Arkady
dc.contributor.authorSonenberg, Nahum
dc.contributor.authorWebster, Nevin R.
dc.contributor.authorDussor, Gregory
dc.contributor.authorCampbell, Zachary T.
dc.contributor.authorPrice, Theodore J.
dc.contributor.utdAuthorMegat, Salim
dc.contributor.utdAuthorRay, Pradipta R.
dc.contributor.utdAuthorMoy, Jamie K.
dc.contributor.utdAuthorLou, Tzu-Fang
dc.contributor.utdAuthorBarragan-Iglesias, Paulino
dc.contributor.utdAuthorPradhan, Grishma
dc.contributor.utdAuthorWanghzou, Andi
dc.contributor.utdAuthorAhmad, Ayesha
dc.contributor.utdAuthorBurton, Michael D.
dc.contributor.utdAuthorDussor, Gregory
dc.contributor.utdAuthorCampbell, Zachary T.
dc.contributor.utdAuthorPrice, Theodore J.
dc.description.abstractNociceptors, sensory neurons in the DRG that detect damaging or potentially damaging stimuli, are key drivers of neuropathic pain. Injury to these neurons causes activation of translation regulation signaling, including the mechanistic target of rapamycin complex 1 (mTORC1) and mitogen-activated protein kinase interacting kinase(MNK) eukaryotic initiation factor (eIF) 4E pathways. This is a mechanism driving changes in excitability of nociceptors that is critical for the generation of chronic pain states; however, the mRNAs that are translated to lead to this plasticity have not been elucidated. To address this gap in knowledge, we used translating ribosome affinity purification in male and female mice to comprehensively characterize mRNA translation in Scn10a-positive nociceptors in chemotherapy-induced neuropathic pain (CIPN) caused by paclitaxel treatment. This unbiased method creates a new resource for the field, confirms many findings in the CIPN literature and also find extensive evidence for new target mechanisms that may cause CIPN. We provide evidence that an underlying mechanism of CIPN is sustained mTORC1 activation driven by MNK1-eIF4E signaling. RagA, aGTPase controlling mTORC1 activity, is identified as a novel target of MNK1-eIF4E signaling. This demonstrates a novel translation regulation signaling circuit wherein MNK1-eIF4E activity drives mTORC1 via control of RagA translation. CIPN and RagA translation are strongly attenuated by genetic ablation of eIF4E phosphorylation, MNK1 elimination or treatment with the MNK inhibitor eFT508. We identify a novel translational circuit for the genesis of neuropathic pain caused by chemotherapy with important implications for therapeutics.
dc.description.departmentSchool of Behavioral and Brain Sciences
dc.description.departmentCenter for Advanced Pain Studies
dc.description.sponsorshipNational Institutes of Health Grants R01NS065926, R01NS098826, R01CA200263, and R01NS100788
dc.identifier.bibliographicCitationMegat, Salim, Pradipta R. Ray, Jamie K. Moy, Tzu-Fang Lou, et al. 2019. "Nociceptor Translational Profiling Reveals the Ragulator-Rag GTPase Complex as a Critical Generator of Neuropathic Pain." Journal Of Neuroscience 39(3): 393-411, doi: 10.1523/JNEUROSCI.2661-18.2018
dc.publisherSoc Neuroscience
dc.rightsCC BY 4.0 (Attribution)
dc.rights©2019 The Authors
dc.source.journalJournal of Neuroscience
dc.subjectNeuropathy (Peripheral)
dc.subjectSensory neurons
dc.subject.meshEukaryotic Initiation Factor-4E
dc.subject.meshMechanistic Target of Rapamycin Complex 1
dc.titleNociceptor Translational Profiling Reveals the Ragulator-Rag GTPase Complex as a Critical Generator of Neuropathic Pain
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