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https://www.readbyqxmd.com/read/28809766/crispr-cas9-editing-of-nf1-gene-identifies-crmp2-as-a-therapeutic-target-in-neurofibromatosis-type-1-related-pain-that-is-reversed-by-s-lacosamide
#1
Aubin Moutal, Xiaofang Yang, Wennan Li, Kerry B Gilbraith, Shizhen Luo, Song Cai, Liberty François-Moutal, Lindsey A Chew, Seul Ki Yeon, Shreya S Bellampalli, Chaoling Qu, Jennifer Y Xie, Mohab M Ibrahim, May Khanna, Ki Duk Park, Frank Porreca, Rajesh Khanna
Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disease linked to mutations of the Nf1 gene. Patients with NF1 commonly experience severe pain. Studies on mice with Nf1 haploinsufficiency have been instructive in identifying sensitization of ion channels as a possible cause underlying the heightened pain suffered by patients with NF1. However, behavioral assessments of Nf1 mice have led to uncertain conclusions about the potential causal role of Nf1 in pain. We used the clustered regularly interspaced short palindromic repeats (CRISPR)-associated 9 (CRISPR/Cas9) genome editing system to create and mechanistically characterize a novel rat model of NF1-related pain...
July 3, 2017: Pain
https://www.readbyqxmd.com/read/28790351/whole-transcriptome-profiling-of-taste-bud-cells
#2
Sunil K Sukumaran, Brian C Lewandowski, Yumei Qin, Ramana Kotha, Alexander A Bachmanov, Robert F Margolskee
Analysis of single-cell RNA-Seq data can provide insights into the specific functions of individual cell types that compose complex tissues. Here, we examined gene expression in two distinct subpopulations of mouse taste cells: Tas1r3-expressing type II cells and physiologically identified type III cells. Our RNA-Seq libraries met high quality control standards and accurately captured differential expression of marker genes for type II (e.g. the Tas1r genes, Plcb2, Trpm5) and type III (e.g. Pkd2l1, Ncam, Snap25) taste cells...
August 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28767512/dissecting-the-role-of-the-crmp2-neurofibromin-complex-on-pain-behaviors
#3
Aubin Moutal, Yue Wang, Xiaofang Yang, Yingshi Ji, Shizhen Luo, Angie Dorame, Shreya S Bellampalli, Lindsey A Chew, Song Cai, Erik T Dustrude, James E Keener, Michael T Marty, Todd W Vanderah, Rajesh Khanna
Neurofibromatosis type 1 (NF1), a genetic disorder linked to inactivating mutations or homozygous deletion of the Nf1 gene, is characterized by tumorigenesis, cognitive dysfunction, seizures, migraine, and pain. Omic studies on human NF1 tissues identified an increase in expression of collapsin response mediator protein 2 (CRMP2), a cytosolic protein reported to regulate the trafficking and activity of presynaptic N-type voltage-gated calcium (Cav2.2) channels. Since neurofibromin, the protein product of the Nf1 gene, binds to and inhibits CRMP2, the neurofibromin-CRMP2 signaling cascade will likely affect Ca2+ channel activity and regulate nociceptive neurotransmission and in vivo responses to noxious stimulation...
July 31, 2017: Pain
https://www.readbyqxmd.com/read/28726921/molecular-dynamics-simulations-and-in-vitro-analysis-of-the-crmp2-thiol-switch
#4
Daniel Möller, Manuela Gellert, Walter Langel, Christopher Horst Lillig
The collapsin response mediator protein CRMP2 (gene: DPYSL2) is crucial for neuronal development. The homotetrameric CRMP2 complex is regulated via two mechanisms: first by phosphorylation and second by the reduction and oxidation of the Cys504 residues of two adjacent subunits. Here, we have analysed the effects of this redox switch on the protein in vitro combined with force field molecular dynamics (MD). Earlier X-ray data reveal the structure of the rigid body of the molecule but lack the flexible C-terminus with the important sites for phosphorylation and redox regulation...
July 20, 2017: Molecular BioSystems
https://www.readbyqxmd.com/read/28660485/crmp2-phosphorylation-drives-glioblastoma-cell-proliferation
#5
Aubin Moutal, Lex Salas Villa, Seul Ki Yeon, Kyle T Householder, Ki Duk Park, Rachael W Sirianni, Rajesh Khanna
Glioblastoma (GBM) is an aggressive primary brain tumor. The rapid growth and the privileged provenance of the tumor within the brain contribute to its aggressivity and poor therapeutic targeting. A poor prognostic factor in glioblastoma is the deletion or mutation of the Nf1 gene. This gene codes for the protein neurofibromin, a tumor suppressor gene that is known to interact with the collapsin response mediator protein 2 (CRMP2). CRMP2 expression and elevated expression of nuclear phosphorylated CRMP2 have recently been implicated in cancer progression...
June 28, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28638064/quantitative-phosphoproteomics-reveals-a-role-for-collapsin-response-mediator-protein-2-in-pdgf-induced-cell-migration
#6
Adil R Sarhan, Justyna Szyroka, Shabana Begum, Michael G Tomlinson, Neil A Hotchin, John K Heath, Debbie L Cunningham
The Platelet Derived Growth Factor (PDGF) family of ligands have well established functions in the induction of cell proliferation and migration during development, tissue homeostasis and interactions between tumours and stroma. However, the mechanisms by which these actions are executed are incompletely understood. Here we report a differential phosphoproteomics study, using a SILAC approach, of PDGF-stimulated mouse embryonic fibroblasts (MEFs). 116 phospho-sites were identified as up-regulated and 45 down-regulated in response to PDGF stimulation...
June 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28630333/boosting-cns-axon-regeneration-by-harnessing-antagonistic-effects-of-gsk3-activity
#7
Marco Leibinger, Anastasia Andreadaki, Renate Golla, Evgeny Levin, Alexander M Hilla, Heike Diekmann, Dietmar Fischer
Implications of GSK3 activity for axon regeneration are often inconsistent, if not controversial. Sustained GSK3 activity in GSK3(S/A) knock-in mice reportedly accelerates peripheral nerve regeneration via increased MAP1B phosphorylation and concomitantly reduces microtubule detyrosination. In contrast, the current study shows that lens injury-stimulated optic nerve regeneration was significantly compromised in these knock-in mice. Phosphorylation of MAP1B and CRMP2 was expectedly increased in retinal ganglion cell (RGC) axons upon enhanced GSK3 activity, but, surprisingly, no GSK3-mediated CRMP2 inhibition was detected in sciatic nerves, thus revealing a fundamental difference between central and peripheral axons...
July 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28616018/collapsin-response-mediator-protein-2-plays-a-major-protective-role-in-acute-axonal-degeneration
#8
REVIEW
Jian-Nan Zhang, Jan C Koch
Axonal degeneration is a key pathological feature in many neurological diseases. It often leads to persistent deficits due to the inability of axons to regenerate in the central nervous system. Therefore therapeutic approaches should optimally both attenuate axonal degeneration and foster axonal regeneration. Compelling evidence suggests that collapsin response mediator protein-2 (CRMP2) might be a molecular target fulfilling these requirements. In this mini-review, we give a compact overview of the known functions of CRMP2 and its molecular interactors in neurite outgrowth and in neurodegenerative conditions...
May 2017: Neural Regeneration Research
https://www.readbyqxmd.com/read/28533518/blocking-crmp2-sumoylation-reverses-neuropathic-pain
#9
A Moutal, E T Dustrude, T M Largent-Milnes, T W Vanderah, M Khanna, R Khanna
No abstract text is available yet for this article.
May 23, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28524835/collapsin-response-mediator-protein-2-induced-retinal-ischemic-injury-in-a-novel-mice-model-of-ocular-ischemia-syndrome
#10
Yu Wang, Xiao-Lei Wang, Guo-Li Xie, Hong-Yang Li, Yan-Ling Wang
BACKGROUND: Collapsin response mediator protein-2 (CRMP2) has been shown to be involved in ischemia/hypoxia (IH) injury. We determined whether CRMP2 modulates ischemic injury in the retinal of Ocular ischemic syndrome (OIS). This study was to explore the molecular mechanisms underlying OIS in a novel mice model. METHODS: Experiments were performed on adult male C57/BL6 mice that received bilateral internal carotid arteries ligation for 1, 2, or 4 weeks. The mice received injection of calpeptin group before occlusion for 4 weeks or not...
June 5, 2017: Chinese Medical Journal
https://www.readbyqxmd.com/read/28500272/probing-the-lithium-response-pathway-in-hipscs-implicates-the-phosphoregulatory-set-point-for-a-cytoskeletal-modulator-in-bipolar-pathogenesis
#11
Brian T D Tobe, Andrew M Crain, Alicia M Winquist, Barbara Calabrese, Hiroko Makihara, Wen-Ning Zhao, Jasmin Lalonde, Haruko Nakamura, Glenn Konopaske, Michelle Sidor, Cameron D Pernia, Naoya Yamashita, Moyuka Wada, Yuuka Inoue, Fumio Nakamura, Steven D Sheridan, Ryan W Logan, Michael Brandel, Dongmei Wu, Joshua Hunsberger, Laurel Dorsett, Cordulla Duerr, Ranor C B Basa, Michael J McCarthy, Namrata D Udeshi, Philipp Mertins, Steven A Carr, Guy A Rouleau, Lina Mastrangelo, Jianxue Li, Gustavo J Gutierrez, Laurence M Brill, Nikolaos Venizelos, Guang Chen, Jeffrey S Nye, Husseini Manji, Jeffrey H Price, Colleen A McClung, Hagop S Akiskal, Martin Alda, De-Maw M Chuang, Joseph T Coyle, Yang Liu, Yang D Teng, Toshio Ohshima, Katsuhiko Mikoshiba, Richard L Sidman, Shelley Halpain, Stephen J Haggarty, Yoshio Goshima, Evan Y Snyder
The molecular pathogenesis of bipolar disorder (BPD) is poorly understood. Using human-induced pluripotent stem cells (hiPSCs) to unravel such mechanisms in polygenic diseases is generally challenging. However, hiPSCs from BPD patients responsive to lithium offered unique opportunities to discern lithium's target and hence gain molecular insight into BPD. By profiling the proteomics of BDP-hiPSC-derived neurons, we found that lithium alters the phosphorylation state of collapsin response mediator protein-2 (CRMP2)...
May 30, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28445771/cyclin-dependent-kinase-5-collapsin-response-mediator-protein-2-pathway-may-mediate-sevoflurane-induced-dendritic-development-abnormalities-in-rat-cortical-neurons
#12
Yafang Liu, Daowei Lin, Chuiliang Liu, Yifan Zhao, Zhiwen Shen, Kun Zhang, Minghui Cao, Yujuan Li
Sevoflurane has been reported to induce neurotoxicity and cognitive impairment in the developing brains. However, the underlying molecular mechanisms remain poorly understood. Recent studies have demonstrated aberrant cyclin-dependent kinase 5 (CDK5) activity is implicated in inhaled anesthetic-induced neurotoxicity. CDK5/CRMP2 signaling is involved in the cortical and hippocampal dendritic development. The aim of present study is to investigate whether the CDK5/CRMP2 pathway mediates sevoflurane-induced dendritic development abnormalities...
April 24, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28366719/minocycline-restores-cognitive-relative-altered-proteins-in-young-bile-duct-ligated-rat-prefrontal-cortex
#13
Shih-Wen Li, Yu-Chieh Chen, Jiunn-Ming Sheen, Mei-Hsin Hsu, You-Lin Tain, Kow-Aung Chang, Li-Tung Huang
AIMS: Bile duct ligation (BDL) model is used to study hepatic encephalopathy accompanied by cognitive impairment. We employed the proteomic analysis approach to evaluate cognition-related proteins in the prefrontal cortex of young BDL rats and analyzed the effect of minocycline on these proteins and spatial memory. MAIN METHODS: BDL was induced in young rats at postnatal day 17. Minocycline as a slow-release pellet was implanted into the peritoneum. Morris water maze test and two-dimensional liquid chromatography-tandem mass spectrometry were used to evaluate spatial memory and prefrontal cortex protein expression, respectively...
July 1, 2017: Life Sciences
https://www.readbyqxmd.com/read/28277940/a-single-structurally-conserved-sumoylation-site-in-crmp2-controls-nav1-7-function
#14
Erik Thomas Dustrude, Samantha Perez-Miller, Liberty François-Moutal, Aubin Moutal, May Khanna, Rajesh Khanna
The neuronal collapsin response mediator protein 2 (CRMP2) undergoes several posttranslational modifications that codify its functions. Most recently, CRMP2 SUMOylation (addition of small ubiquitin like modifier (SUMO)) was identified as a key regulatory step within a modification program that codes for CRMP2 interaction with, and trafficking of, voltage-gated sodium channel NaV1.7. In this paper, we illustrate the utility of combining sequence alignment within protein families with structural analysis to identify, from several putative SUMOylation sites, those that are most likely to be biologically relevant...
July 4, 2017: Channels
https://www.readbyqxmd.com/read/28161890/homology-guided-mutational-analysis-reveals-the-functional-requirements-for-antinociceptive-specificity-of-collapsin-response-mediator-protein-2-derived-peptides
#15
Aubin Moutal, Wennan Li, Yue Wang, Weina Ju, Shizhen Luo, Song Cai, Liberty François-Moutal, Samantha Perez-Miller, Jackie Hu, Erik T Dustrude, Todd W Vanderah, Vijay Gokhale, May Khanna, Rajesh Khanna
BACKGROUND AND PURPOSE: N-type voltage-gated calcium (Cav 2.2) channels are critical determinants of increased neuronal excitability and neurotransmission accompanying persistent neuropathic pain. Although Cav 2.2 channel antagonists are recommended as first-line treatment for neuropathic pain, calcium-current blocking gabapentinoids inadequately alleviate chronic pain symptoms and often exhibit numerous side effects. Collapsin response mediator protein 2 (CRMP2) targets Cav 2.2 channels to the sensory neuron membrane and allosterically modulates their function...
February 5, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/27940916/hierarchical-crmp2-posttranslational-modifications-control-nav1-7-function
#16
Erik T Dustrude, Aubin Moutal, Xiaofang Yang, Yuying Wang, May Khanna, Rajesh Khanna
Voltage-gated sodium channels are crucial determinants of neuronal excitability and signaling. Trafficking of the voltage-gated sodium channel NaV1.7 is dysregulated in neuropathic pain. We identify a trafficking program for NaV1.7 driven by hierarchical interactions with posttranslationally modified versions of the binding partner collapsin response mediator protein 2 (CRMP2). The binding described between CRMP2 and NaV1.7 was enhanced by conjugation of CRMP2 with small ubiquitin-like modifier (SUMO) and further controlled by the phosphorylation status of CRMP2...
December 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27917413/efficacy-of-s-lacosamide-in-preclinical-models-of-cephalic-pain
#17
Aubin Moutal, Nathan Eyde, Edwin Telemi, Ki Duk Park, Jennifer Y Xie, David W Dodick, Frank Porreca, Rajesh Khanna
Migraine is one of the world's most common neurological disorders. Current acute migraine treatments have sub-optimal efficacy and new therapeutic options are needed. Approaches targeting calcitonin gene related peptide (CGRP) signaling are clinically effective but small molecule antagonists have not been advanced due to toxicity. In this study, we explored the axonal growth/specification collapsin response mediator protein 2 (CRMP2) as a novel "druggable" target for inhibiting CGRP release and for potential relevance for treatment of migraine pain...
June 2016: Pain Reports (Baltimore, Md.)
https://www.readbyqxmd.com/read/27849007/two-ptp-receptors-mediate-cspg-inhibition-by-convergent-and-divergent-signaling-pathways-in-neurons
#18
Yosuke Ohtake, Daniella Wong, P M Abdul-Muneer, Michael E Selzer, Shuxin Li
Receptor protein tyrosine phosphatase σ (PTPσ) and its subfamily member LAR act as transmembrane receptors that mediate growth inhibition of chondroitin sulfate proteoglycans (CSPGs). Inhibition of either receptor increases axon growth into and beyond scar tissues after CNS injury. However, it is unclear why neurons express two similar CSPG receptors, nor whether they use the same or different intracellular pathways. We have now studied the signaling pathways of these two receptors using N2A cells and primary neurons derived from knockout mice...
November 16, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27845394/calpain-mediated-cleavage-of-collapsin-response-mediator-protein-2-drives-acute-axonal-degeneration
#19
Jian-Nan Zhang, Uwe Michel, Christof Lenz, Caroline C Friedel, Sarah Köster, Zara d'Hedouville, Lars Tönges, Henning Urlaub, Mathias Bähr, Paul Lingor, Jan C Koch
Axonal degeneration is a key initiating event in many neurological diseases. Focal lesions to axons result in a rapid disintegration of the perilesional axon by acute axonal degeneration (AAD) within several hours. However, the underlying molecular mechanisms of AAD are only incompletely understood. Here, we studied AAD in vivo through live-imaging of the rat optic nerve and in vitro in primary rat cortical neurons in microfluidic chambers. We found that calpain is activated early during AAD of the optic nerve and that calpain inhibition completely inhibits axonal fragmentation on the proximal side of the crush while it attenuates AAD on the distal side...
November 15, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27801893/the-dpysl2-gene-connects-mtor-and-schizophrenia
#20
X Pham, G Song, S Lao, L Goff, H Zhu, D Valle, D Avramopoulos
We previously reported a schizophrenia-associated polymorphic CT di-nucleotide repeat (DNR) at the 5'-untranslated repeat (UTR) of DPYSL2, which responds to mammalian target of Rapamycin (mTOR) signaling with allelic differences in reporter assays. Now using microarray analysis, we show that the DNR alleles interact differentially with specific proteins, including the mTOR-related protein HuD/ELAVL4. We confirm the differential binding to HuD and other known mTOR effectors by electrophoretic mobility shift assays...
November 1, 2016: Translational Psychiatry
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