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Amino acid sequence conservation of the algesic fragment of myelin basic protein is required for its interaction with CDK5 and function in pain.

ABSTRACT: Neurotrauma frequently results in neuropathic pain. Our earlier studies revealed that peripheral neurotrauma-induced fragmentation of the myelin basic protein (MBP), a major component of the myelin sheath formed by Schwann cells, initiates a pain response from light touch stimuli (mechanical allodynia) in rodents. Here, we identified the cyclin-dependent kinase 5 (CDK5), as an intracellular interactor of MBP in Schwann cells. The algesic peptide fragment of MBP directly associated with CDK5. When complexed with its p25 coactivator, CDK5 phosphorylated the conserved MBP sequence. The expressed MBP fragment colocalized with CDK5 in Schwann cell protrusions. Roscovitine, an ATP-competitive CDK5 inhibitor, disrupted localization of the expressed MBP peptide. Mutations in the evolutionary conserved MBP algesic sequence resulted in the interference with intracellular trafficking of the MBP fragment and kinase activity of CDK5 and diminished pain-like behavior in rodents. Our findings show that MBP fragment amino acid sequence conservation determines its interactions, trafficking, and pronociceptive activity. Because CDK5 activity controls both neurogenesis and nociception, the algesic MBP fragment may be involved in the regulation of the CDK5 functionality in pain signaling and postinjury neurogenesis in vertebrates.

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The novel RNA-seq datasets were deposited in the GEO database under the accession number GSE107020.

SUBMITTER: Chernov AV

PROVIDER: S-EPMC6288010 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Amino acid sequence conservation of the algesic fragment of myelin basic protein is required for its interaction with CDK5 and function in pain.

Chernov Andrei V AV Remacle Albert G AG Hullugundi Swathi K SK Cieplak Piotr P Angert Mila M Dolkas Jennifer J Shubayev Veronica I VI Strongin Alex Y AY

The FEBS journal 20180827 18

Neurotrauma frequently results in neuropathic pain. Our earlier studies revealed that peripheral neurotrauma-induced fragmentation of the myelin basic protein (MBP), a major component of the myelin sheath formed by Schwann cells, initiates a pain response from light touch stimuli (mechanical allodynia) in rodents. Here, we identified the cyclin-dependent kinase 5 (CDK5), as an intracellular interactor of MBP in Schwann cells. The algesic peptide fragment of MBP directly associated with CDK5. Whe ...[more]

PMID: 30079618

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Project description:BACKGROUND:The myelin sheath provides electrical insulation of mechanosensory A?-afferent fibers. Myelin-degrading matrix metalloproteinases (MMPs) damage the myelin sheath. The resulting electrical instability of A?-fibers is believed to activate the nociceptive circuitry in A?-fibers and initiate pain from innocuous tactile stimulation (mechanical allodynia). The precise molecular mechanisms, responsible for the development of this neuropathic pain state after nerve injury (for example, chronic constriction injury, CCI), are not well understood. METHODS AND RESULTS:Using mass spectrometry of the whole sciatic nerve proteome followed by bioinformatics analyses, we determined that the pathways, which are classified as the Infectious Disease and T-helper cell signaling, are readily activated in the nerves post-CCI. Inhibition of MMP-9/MMP-2 suppressed CCI-induced mechanical allodynia and concomitant TNF-? and IL-17A expression in nerves. MMP-9 proteolysis of myelin basic protein (MBP) generated the MBP84-104 and MBP68-86 digest peptides, which are prominent immunogenic epitopes. In agreement, the endogenous MBP69-86 epitope co-localized with MHCII and MMP-9 in Schwann cells and along the nodes of Ranvier. Administration of either the MBP84-104 or MBP68-86 peptides into the naïve nerve rapidly produced robust mechanical allodynia with a concomitant increase in T cells and MHCII-reactive cell populations at the injection site. As shown by the genome-wide expression profiling, a single intraneural MBP84-104 injection stimulated the inflammatory, immune cell trafficking, and antigen presentation pathways in the injected naïve nerves and the associated spinal cords. Both MBP84-104-induced mechanical allodynia and characteristic pathway activation were remarkably less prominent in the T cell-deficient athymic nude rats. CONCLUSIONS:These data implicate MBP as a novel mediator of pain. Furthermore, the action of MMPs expressed within 1?day post-injury is critical to the generation of tactile allodynia, neuroinflammation, and the immunodominant MBP digest peptides in nerve. These MBP peptides initiate mechanical allodynia in both a T cell-dependent and -independent manner. In the course of Wallerian degeneration, the repeated exposure of the cryptic MBP epitopes, which are normally sheltered from immunosurveillance, may induce the MBP-specific T cell clones and a self-sustaining immune reaction, which may together contribute to the transition of acute pain into a chronic neuropathic pain state.

Dataset Information

Amino acid sequence conservation of the algesic fragment of myelin basic protein is required for its interaction with CDK5 and function in pain.

Database

Publications

Amino acid sequence conservation of the algesic fragment of myelin basic protein is required for its interaction with CDK5 and function in pain.

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