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

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  • Additional Information
    • Source:
      Publisher: Society for Neuroscience Country of Publication: United States NLM ID: 8102140 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1529-2401 (Electronic) Linking ISSN: 02706474 NLM ISO Abbreviation: J Neurosci Subsets: MEDLINE
    • Publication Information:
      Publication: Washington, DC : Society for Neuroscience
      Original Publication: [Baltimore, Md.] : The Society, c1981-
    • Subject Terms:
      Gene Expression Profiling* ; Nociceptors*; Mice, Knockout/*genetics ; Monomeric GTP-Binding Proteins/*genetics ; Neuralgia/*genetics; Animals ; Antineoplastic Agents, Phytogenic ; Eukaryotic Initiation Factor-4E/genetics ; Female ; Male ; Mechanistic Target of Rapamycin Complex 1/genetics ; Mice ; Mice, Transgenic ; NAV1.8 Voltage-Gated Sodium Channel/genetics ; Neuralgia/chemically induced ; Neuralgia/psychology ; Paclitaxel ; Pain Measurement ; Protein Serine-Threonine Kinases/genetics ; Ribosomes/chemistry ; Signal Transduction/genetics
    • Abstract:
      Nociceptors, 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, a GTPase 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. SIGNIFICANCE STATEMENT Neuropathic pain affects up to 10% of the population, but its underlying mechanisms are incompletely understood, leading to poor treatment outcomes. We used translating ribosome affinity purification technology to create a comprehensive translational profile of DRG nociceptors in naive mice and at the peak of neuropathic pain induced by paclitaxel treatment. We reveal new insight into how mechanistic target of rapamycin complex 1 is activated in neuropathic pain pointing to a key role of MNK1-eIF4E-mediated translation of a complex of mRNAs that control mechanistic target of rapamycin complex 1 signaling at the surface of the lysosome. We validate this finding using genetic and pharmacological techniques. Our work strongly suggests that MNK1-eIF4E signaling drives CIPN and that a drug in human clinical trials, eFT508, may be a new therapeutic for neuropathic pain.
      (Copyright © 2019 the authors 0270-6474/19/390394-19$15.00/0.)
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    • Grant Information:
      R01 NS098826 United States NS NINDS NIH HHS; K22 NS096030 United States NS NINDS NIH HHS; R01 NS065926 United States NS NINDS NIH HHS; R01 CA200263 United States CA NCI NIH HHS; R01 NS100788 United States NS NINDS NIH HHS
    • Contributed Indexing:
      Keywords: TRAP; eIF4E; mTOR; neuropathic pain; nociceptor
    • Accession Number:
      0 (Antineoplastic Agents, Phytogenic)
      0 (Eukaryotic Initiation Factor-4E)
      0 (NAV1.8 Voltage-Gated Sodium Channel)
      0 (RagA protein, mouse)
      0 (Scn10a protein, mouse)
      EC 2.7.1.- (Mknk1 protein, mouse)
      EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
      EC 2.7.11.1 (Protein Serine-Threonine Kinases)
      EC 3.6.5.2 (Monomeric GTP-Binding Proteins)
      P88XT4IS4D (Paclitaxel)
    • Publication Date:
      Date Created: 20181122 Date Completed: 20191016 Latest Revision: 20231005
    • Publication Date:
      20231215
    • Accession Number:
      PMC6335757
    • Accession Number:
      10.1523/JNEUROSCI.2661-18.2018
    • Accession Number:
      30459229