Peptides encoded by 5’ untranslated regions mediate pain sensitization
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA480907 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7516860.fastq.gz | Fastqsanger.gz | |||
| SRR7516861.fastq.gz | Fastqsanger.gz | |||
| SRR7516862.fastq.gz | Fastqsanger.gz | |||
| SRR7516853.fastq.gz | Fastqsanger.gz | |||
| SRR7516863.fastq.gz | Fastqsanger.gz |
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Project description:Nociceptors are neurons responsible for the detection of pain producing stimuli. Persistent changes in their activity, termed plasticity, benefit survival through injury avoidance and are regulated on a translational basis. Yet, the mRNAs whose translation facilitates plasticity are unknown. Here, we apply ribosome profiling to dorsal root ganglion and identify a small number of transcripts that are selectively translated in response to plasticity mediators. Among them are Arc and Fos, genes implicated in episodic learning in the brain. We demonstrate that the ribosomal S6 kinase 1 is responsible for their production in nociceptors. Blocking S6 driven translation also reduces pain associated behavioral responses in vivo. In addition to translation of coding regions of mRNA, we detect pervasive ribosome occupancy in 5’ untranslated regions. We find that peptides encoded by open reading frames in the 5’ untranslated regions of Calca and Egr2 increase neuronal excitability in vitro and are sufficient to induce pain-like behaviors in vivo. Together, our findings uncover new targets of translational control that drive changes in plasticity and suggest new mechanisms for targeted pain therapeutics that disrupt pain signaling.
2020-02-01 | GSE117043 | GEO
Project description:AbstractTranslational regulation permeates neuronal function. Nociceptors are sensory neurons responsible for the detection of harmful stimuli. Changes in their activity, termed plasticity, are intimately linked to the persistence of pain. Although inhibitors of protein synthesis robustly attenuate pain-associated behavior, the underlying targets that support plasticity are largely unknown. Here, we examine the contribution of protein synthesis in regions of RNA annotated as noncoding. Based on analyses of previously reported ribosome profiling data, we provide evidence for widespread translation in noncoding transcripts and regulatory regions of mRNAs. We identify an increase in ribosome occupancy in the 5' untranslated regions of the calcitonin gene-related peptide (CGRP/Calca). We validate the existence of an upstream open reading frame (uORF) using a series of reporter assays. Fusion of the uORF to a luciferase reporter revealed active translation in dorsal root ganglion neurons after nucleofection. Injection of the peptide corresponding to the calcitonin gene-related peptide-encoded uORF resulted in pain-associated behavioral responses in vivo and nociceptor sensitization in vitro. An inhibitor of heterotrimeric G protein signaling blocks both effects. Collectively, the data suggest pervasive translation in regions of the transcriptome annotated as noncoding in dorsal root ganglion neurons and identify a specific uORF-encoded peptide that promotes pain sensitization through GPCR signaling.
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Project description:Many eukaryotic RNAs have been considered non-coding as they only contain short open reading frames (sORFs). There is increasing evidence for the translation of these sORFs into bioactive peptides. Yet only a few small peptides are annotated in the model organism Arabidopsis thaliana. To aid the functional annotation of small peptides, we have developed ARA-PEPs, a repository and webserver of putative peptides encoded by sORFs in the Arabidopsis genome from in house Tiling arrays, RNA sequencing and from publicly available datasets. In order to identify novel oxidative stress-induced peptides in Arabidopsis thaliana a tiling array analysis (GeneChip® Arabidopsis Tiling 1.0R Arrays ) was performed on mRNA extracted from leaves inoculated with Botrytis cinerea (BC). Normalized log signals were obtained using the Affymetrix Tiling Analysis Software - Version 1.1, Build 2. ON and OFF probes were selected using a threshold, based on positive controls. Next, groups of 4-13 successive ON probes were combined into short TARs and a selection was made of TARs having an average signal intensity at least 2.6-fold higher after BC treatment compared to the control treatment, resulting in 195 BC induced TARs.
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Project description:Sensitization of spinal nociceptive circuits plays a cardinal role in neuropathic pain. This sensitization depends on new gene expression that is primarily regulated via transcriptional and translational control mechanisms. The relative roles of these mechanisms in regulating gene expression in the clinically relevant chronic phase of neuropathic pain are not well understood. Here, we show that changes in gene expression in the spinal cord during the chronic phase of neuropathic pain are substantially regulated at the translational level. Downregulating spinal translation at the chronic phase alleviated pain hypersensitivity. Cell-type-specific profiling revealed that spinal inhibitory neurons exhibited greater changes in translation after peripheral nerve injury compared to excitatory neurons. Notably, increasing translation selectively in all inhibitory neurons or parvalbumin-positive (PV + ) interneurons, but not excitatory neurons, promoted mechanical pain hypersensitivity. Furthermore, increasing translation in PV + neurons decreased their intrinsic excitability and spiking activity, whereas reducing translation in spinal PV + neurons prevented the nerve injury-induced decrease in excitability. Thus, translational control mechanisms in the spinal cord, primarily in inhibitory neurons, play a critical role in mediating neuropathic pain hypersensitivity.
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Project description:Recent studies reveal that microglia modulate synaptic transmission by direct synaptic pruning. Microglia reactivation is a crucial mechanism of central sensitization in neuropathic pain, yet the exact changes of microglia during the development of neuropathic pain and its interaction with the spinal inhibitory circuits remains unclear. In this work, single-cell sequencing delineates temporal changes in spinal microglia and identifies a specific type of microglia as the subpopulation mediating synaptic pruning. We found that peripheral nerve injury induced the transition of spinal microglia from a pro-inflammatory to a “pruning” state, resulting in pain hypersensitivity by spinal disinhibition.
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Project description:Neuropathic pain is a refractory condition that involves de novo protein synthesis in the nociceptive pathway. The mechanistic target of rapamycin (mTOR) is a master regulator of protein synthesis; however, mechanisms underlying its role in neuropathic pain remain elusive. Using spared nerve injury-induced neuropathic pain model, we found mTOR activation in large-diameter dorsal root ganglion (DRG) neurons and spinal microglia. However, selective ablation of mTOR in DRG neurons, rather than microglia, alleviated neuropathic pain. Combining transcriptomic profiling, electrophysiological recording and pharmacologic manipulations, we demonstrated that activated mTOR promoted neuropeptide Y (NPY) induction in mechanoreceptors and that NPY acted on Y2 receptors (Y2R) but not Y1R to enhance nociceptor excitability. Peripheral replenishment of NPY reversed pain alleviation upon mTOR removal, whereas Y2R antagonists prevented its function. Our findings reveal an unexpected link between mTOR and NPY in promoting nociceptor sensitization and neuropathic pain, through NPY/Y2R signaling-mediated intra-ganglionic transmission.
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Project description:Genomics of Pain - Resilience to Pain
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Project description:Nociceptive neurons respond to inflammation, initiating protective reflexes and alerting the host. Here we found that TRPV1 nociceptors express and activate the cytosolic DNA-sensing protein Stimulator of Interferon Genes (STING) in response to inflammation. Neuronal activation of STING promotes signaling through TBK1 and triggers a Type I interferon (IFN-I) response. The absence of STING led to heightened pain responses to chemical irritants or heat. In contrast, mice expressing a nociceptor-specific gain-of-function mutation in STING exhibited an IFN gene signature that reduced nociceptor excitability and inflammatory hyperalgesia. Importantly, several IFN-regulated genes (IRGs) were specific to nociceptor ion channels responsible for controlling neuronal activity and pain threshold. Therefore, STING promotes a pain-resolving IFN-I signaling pathway in nociceptors, thereby preventing sensitization and persistent pain
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