GSE113941
Nociceptor translational profiling reveals the RagA-mTORC1 network as a critical generator of neuropathic pain
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. Overall design: Examination of paired unbiased mRNA profile and mRNA profile based on eGFP + L10a (RPL10A) pulldown (TRAP assay) for normal mouse DRG (4 assays / replicates) and DRG from CIPN (Paclitaxel) model mouse (5 assays, 2 pooled to make 4 replicates) Associated NIH grants: R01NS065926 (TJP), R01NS098826 (TJP and GD), R01CA200263 (PMD) and R01NS100788 (ZTC)