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An understudied symptom of the genetic disorder Neurofibromatosis type 1 (NF1) is chronic idiopathic pain. We used targeted editing of Nf1 in rats to provide direct evidence of a causal relationship between neurofibromin, the protein product of the Nf1 gene, and pain responses. Our study data identified a protein-interaction network with collapsin response meditator protein 2 (CRMP2) as a node and neurofibromin, syntaxin 1A, and the N-type voltage-gated calcium (CaV2.2) channel as interaction edges. Neurofibromin uncouples CRMP2 from syntaxin 1A. Upon loss/mutation of neurofibromin, as seen in patients with NF1, the CRMP2/Neurofibromin interaction is uncoupled, which frees CRMP2 to interact with both syntaxin 1A and CaV2.2, culminating in increased release of the pro-nociceptive neurotransmitter calcitonin gene-related peptide (CGRP). Our work also identified the CRMP2-derived peptide CNRP1, which uncoupled CRMP2's interactions with neurofibromin, syntaxin 1A, as well as CaV2.2. Here, we tested if CRISPR/Cas9-mediated editing of the Nf1 gene, which leads to functional remodeling of peripheral nociceptors through effects on the tetrodotoxin-sensitive (TTX-S) Na+ voltage-gated sodium channel (NaV1.7) and CaV2.2, could be affected using CNRP1, a peptide designed to target the CRMP2-neurofibromin interface. The data presented here shows that disrupting the CRMP2-neurofibromin interface is sufficient to reverse the dysregulations of voltage-gated ion channels and neurotransmitter release elicited by Nf1 gene editing. As a consequence of these effects, the CNRP1 peptide reversed hyperalgesia to thermal stimulation of the hindpaw observed in Nf1-edited rats. Our findings support future pharmacological targeting of the CRMP2/neurofibromin interface for NF1-related pain relief.
Pubmed ID: 29655575 RIS Download
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A national mouse monoclonal antibody generating resource for biochemical and immunohistochemical applications in mammalian brain. NeuroMabs are generated from mice immunized with synthetic and recombinant immunogens corresponding to components of the neuronal proteome as predicted from genomic and other large-scale cloning efforts. Comprehensive biochemical and immunohistochemical analyses of human, primate and non-primate mammalian brain are incorporated into the initial NeuroMab screening procedure. This yields a subset of mouse mAbs that are optimized for use in brain (i.e. NeuroMabs): for immunocytochemical-based imaging studies of protein localization in adult, developing and pathological brain samples, for biochemical analyses of subunit composition and post-translational modifications of native brain proteins, and for proteomic analyses of native brain protein networks. The NeuroMab facility was initially funded with a five-year U24 cooperative grant from NINDS and NIMH. The initial goal of the facility for this funding period is to generate a library of novel NeuroMabs against neuronal proteins, initially focusing on membrane proteins (receptors/channels/transporters), synaptic proteins, other neuronal signaling molecules, and proteins with established links to disease states. The scope of the facility was expanded with supplements from the NIH Blueprint for Neuroscience Research to include neurodevelopmental targets, the NIH Roadmap for Medical Research to include epigenetics targets, and NIH Office of Rare Diseases Research to include rare disease targets. These NeuroMabs will then be produced on a large scale and made available to the neuroscience research community on an inexpensive basis as tissue culture supernatants or purified immunoglobulin by Antibodies Inc. The UC Davis/NIH NeuroMab Facility makes NeuroMabs available directly to end users and is unable to accommodate sales to distributors for third party distribution. Note, NeuroMab antibodies are now offered through antibodiesinc.
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