Taking Pain Out of NGF: A “Painless” NGF Mutant, Linked to Hereditary Sensory Autonomic Neuropathy Type V, with Full Neurotrophic Activity
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{"title"=>"Taking pain out of ngf: A \"painless\" ngf mutant, linked to hereditary sensory autonomic neuropathy type v, with full neurotrophic activity", "type"=>"journal", "authors"=>[{"first_name"=>"Simona", "last_name"=>"Capsoni", "scopus_author_id"=>"6602808790"}, {"first_name"=>"Sonia", "last_name"=>"Covaceuszach", "scopus_author_id"=>"6602454818"}, {"first_name"=>"Sara", "last_name"=>"Marinelli", "scopus_author_id"=>"56418177300"}, {"first_name"=>"Marcello", "last_name"=>"Ceci", "scopus_author_id"=>"23092666900"}, {"first_name"=>"Antonietta", "last_name"=>"Bernardo", "scopus_author_id"=>"7006078218"}, {"first_name"=>"Luisa", "last_name"=>"Minghetti", "scopus_author_id"=>"7004899724"}, {"first_name"=>"Gabriele", "last_name"=>"Ugolini", "scopus_author_id"=>"8241263100"}, {"first_name"=>"Flaminia", "last_name"=>"Pavone", "scopus_author_id"=>"7006259647"}, {"first_name"=>"Antonino", "last_name"=>"Cattaneo", "scopus_author_id"=>"15829214500"}], "year"=>2011, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "scopus"=>"2-s2.0-79952233342", "sgr"=>"79952233342", "pui"=>"361364872", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "pmid"=>"21387003", "doi"=>"10.1371/journal.pone.0017321"}, "id"=>"9f5f6c5c-e5ba-3015-9f17-ea2a017f4a94", "abstract"=>"During adulthood, the neurotrophin Nerve Growth Factor (NGF) sensitizes nociceptors, thereby increasing the response to noxious stimuli. The relationship between NGF and pain is supported by genetic evidence: mutations in the NGF TrkA receptor in patients affected by an hereditary rare disease (Hereditary Sensory and Autonomic Neuropathy type IV, HSAN IV) determine a congenital form of severe pain insensitivity, with mental retardation, while a mutation in NGFB gene, leading to the aminoacid substitution R100W in mature NGF, determines a similar loss of pain perception, without overt cognitive neurological defects (HSAN V). The R100W mutation provokes a reduced processing of proNGF to mature NGF in cultured cells and a higher percentage of neurotrophin secreted is in the proNGF form. Moreover, using Surface Plasmon Resonance we showed that the R100W mutation does not affect NGF binding to TrkA, while it abolishes NGF binding to p75NTR receptors. However, it remains to be clarified whether the major impact of the mutation is on the biological function of proNGF or of mature NGF and to what extent the effects of the R100W mutation on the HSAN V clinical phenotype are developmental, or whether they reflect an impaired effectiveness of NGF to regulate and mediate nociceptive transmission in adult sensory neurons. Here we show that the R100 mutation selectively alters some of the signaling pathways activated downstream of TrkA NGF receptors. NGFR100 mutants maintain identical neurotrophic and neuroprotective properties in a variety of cell assays, while displaying a significantly reduced pain-inducing activity in vivo (n = 8-10 mice/group). We also show that proNGF has a significantly reduced nociceptive activity, with respect to NGF. Both sets of results jointly contribute to elucidating the mechanisms underlying the clinical HSAN V manifestations, and to clarifying which receptors and intracellular signaling cascades participate in the pain sensitizing action of NGF.", "link"=>"http://www.mendeley.com/research/taking-pain-ngf-painless-ngf-mutant-linked-hereditary-sensory-autonomic-neuropathy-type-v-full-neuro", "reader_count"=>66, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>3, "Student > Doctoral Student"=>2, "Researcher"=>19, "Student > Ph. D. Student"=>14, "Student > Postgraduate"=>3, "Student > Master"=>5, "Other"=>2, "Student > Bachelor"=>11, "Professor"=>5}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>3, "Student > Doctoral Student"=>2, "Researcher"=>19, "Student > Ph. D. Student"=>14, "Student > Postgraduate"=>3, "Student > Master"=>5, "Other"=>2, "Student > Bachelor"=>11, "Professor"=>5}, "reader_count_by_subject_area"=>{"Unspecified"=>3, "Biochemistry, Genetics and Molecular Biology"=>5, "Nursing and Health Professions"=>1, "Agricultural and Biological Sciences"=>26, "Medicine and Dentistry"=>7, "Neuroscience"=>10, "Pharmacology, Toxicology and Pharmaceutical Science"=>4, "Chemistry"=>6, "Psychology"=>3, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>7}, "Neuroscience"=>{"Neuroscience"=>10}, "Chemistry"=>{"Chemistry"=>6}, "Psychology"=>{"Psychology"=>3}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>26}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Unspecified"=>{"Unspecified"=>3}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>4}}, "reader_count_by_country"=>{"Sweden"=>1, "Brazil"=>1, "United Kingdom"=>2, "Mexico"=>1, "Germany"=>1}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/794651"], "description"=>"<p>Western blot and densitometric analysis of (A) TrkA (Y490), (B)\n Akt/S473), and (C) PLC-γ1 (Y783) phosphorylation, in extracts from\n BALB/C 3T3 TrkA cells, stimulated by 100 ng/ml of hNGF and hNGFR100\n mutants. D, Western blot of phospho-TrkA (Y490), Akt (S473), PLC-γ1\n (Y783) and Erks (T204/Y202) in PC12 cells, stimulated by 5 ng/ml of hNGF\n and hNGFR100E mutant. E, Densitometric analysis of phospho-TrkA. F,\n Densitometric analysis of phospho-Akt. G, Densitometric analysis of\n phospho-PLC-γ1. H, Densitometric analysis of phospho-Erks. I,\n Densitometric analysis of phospho c-jun in hippocampal neurons. The\n experiments were performed in triplicate. Bars represent the mean\n ± s.e.m.</p>", "links"=>[], "tags"=>["trka", "p75ntr", "signaling", "hngf"], "article_id"=>465018, "categories"=>["Neuroscience"], "users"=>["Simona Capsoni", "Sonia Covaceuszach", "Sara Marinelli", "Marcello Ceci", "Antonietta Bernardo", "Luisa Minghetti", "Gabriele Ugolini", "Flaminia Pavone", "Antonino Cattaneo"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0017321.g001", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Activation_of_TrkA_and_p75NTR_signaling_by_hNGF_mutants_/465018", "title"=>"Activation of TrkA and p75NTR signaling by hNGF mutants.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-02-28 01:23:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/795239"], "description"=>"<p>(A) Mechanical allodynia: dose-response allodynic effects of hNGF after\n intraplantar injection in the hindpaw. (B) Mechanical allodynia: reduced\n allodynic response 5 hours after intraplantar injection of 4\n µg/mouse of hNGFR100E compared to hNGF. (C) Thermal hyperalgesic\n effects in mice injected with hNGFR100E compared to hNGF. (D) Mechanical\n allodynia: reduced allodynic effects of intraplantar injection of\n hproNGF versus hNGF, and of hproNGF mutant R100E versus hproNGF. Points\n represent mean of absolute values ± s.e.m. ANOVA plus post-hoc\n Tukey-Kramer test; * p<0.001 versus saline, # p<0.01 hNGFR100E\n versus hNGF.</p>", "links"=>[], "tags"=>["pro-nociceptive", "responses", "hngf"], "article_id"=>465607, "categories"=>["Neuroscience"], "users"=>["Simona Capsoni", "Sonia Covaceuszach", "Sara Marinelli", "Marcello Ceci", "Antonietta Bernardo", "Luisa Minghetti", "Gabriele Ugolini", "Flaminia Pavone", "Antonino Cattaneo"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0017321.g005", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Reduced_pro_nociceptive_responses_of_hNGF_mutants_/465607", "title"=>"Reduced pro-nociceptive responses of hNGF mutants.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-02-28 01:33:27"}
  • {"files"=>["https://ndownloader.figshare.com/files/397635", "https://ndownloader.figshare.com/files/397639", "https://ndownloader.figshare.com/files/397649", "https://ndownloader.figshare.com/files/397653", "https://ndownloader.figshare.com/files/397660", "https://ndownloader.figshare.com/files/397667", "https://ndownloader.figshare.com/files/397672", "https://ndownloader.figshare.com/files/397677", "https://ndownloader.figshare.com/files/397697"], "description"=>"<div><p>During adulthood, the neurotrophin Nerve Growth Factor (NGF) sensitizes nociceptors, thereby increasing the response to noxious stimuli. The relationship between NGF and pain is supported by genetic evidence: mutations in the NGF TrkA receptor in patients affected by an hereditary rare disease (Hereditary Sensory and Autonomic Neuropathy type IV, HSAN IV) determine a congenital form of severe pain insensitivity, with mental retardation, while a mutation in <em>NGFB</em> gene, leading to the aminoacid substitution <em>R100W</em> in mature NGF, determines a similar loss of pain perception, without overt cognitive neurological defects (HSAN V). The R100W mutation provokes a reduced processing of proNGF to mature NGF in cultured cells and a higher percentage of neurotrophin secreted is in the proNGF form. Moreover, using Surface Plasmon Resonance we showed that the R100W mutation does not affect NGF binding to TrkA, while it abolishes NGF binding to p75NTR receptors. However, it remains to be clarified whether the major impact of the mutation is on the biological function of proNGF or of mature NGF and to what extent the effects of the R100W mutation on the HSAN V clinical phenotype are developmental, or whether they reflect an impaired effectiveness of NGF to regulate and mediate nociceptive transmission in adult sensory neurons. Here we show that the R100 mutation selectively alters some of the signaling pathways activated downstream of TrkA NGF receptors. NGFR100 mutants maintain identical neurotrophic and neuroprotective properties in a variety of cell assays, while displaying a significantly reduced pain-inducing activity <em>in vivo</em> (n = 8–10 mice/group). We also show that proNGF has a significantly reduced nociceptive activity, with respect to NGF. Both sets of results jointly contribute to elucidating the mechanisms underlying the clinical HSAN V manifestations, and to clarifying which receptors and intracellular signaling cascades participate in the pain sensitizing action of NGF.</p> </div>", "links"=>[], "tags"=>["taking", "ngf", "linked", "hereditary", "sensory", "autonomic", "neuropathy", "neurotrophic"], "article_id"=>138549, "categories"=>["Neuroscience"], "users"=>["Simona Capsoni", "Sonia Covaceuszach", "Sara Marinelli", "Marcello Ceci", "Antonietta Bernardo", "Luisa Minghetti", "Gabriele Ugolini", "Flaminia Pavone", "Antonino Cattaneo"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0017321.s001", "https://dx.doi.org/10.1371/journal.pone.0017321.s002", "https://dx.doi.org/10.1371/journal.pone.0017321.s003", "https://dx.doi.org/10.1371/journal.pone.0017321.s004", "https://dx.doi.org/10.1371/journal.pone.0017321.s005", "https://dx.doi.org/10.1371/journal.pone.0017321.s006", "https://dx.doi.org/10.1371/journal.pone.0017321.s007", "https://dx.doi.org/10.1371/journal.pone.0017321.s008", "https://dx.doi.org/10.1371/journal.pone.0017321.s009"], "stats"=>{"downloads"=>9, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Taking_Pain_Out_of_NGF_A_Painless_NGF_Mutant_Linked___to_Hereditary_Sensory_Autonomic_Neuropathy_Type_V_with_Full_Neurotrophic___Activity/138549", "title"=>"Taking Pain Out of NGF: A “Painless” NGF Mutant, Linked\n to Hereditary Sensory Autonomic Neuropathy Type V, with Full Neurotrophic\n Activity", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2011-02-28 02:22:29"}
  • {"files"=>["https://ndownloader.figshare.com/files/794797"], "description"=>"<p>In Panels A–C, PC12 cells were plated in presence of 100 ng/ml of\n hNGF (B) or hNGFR100E (C) and the number of PC12 processes evaluated\n (J). In panels D-F, PC12cells were primed with 50 ng/ml of hNGF (E) or\n hNGFR100E (F) for 1 week and replated for 2 days in presence of 10 ng/ml\n of either hNGF or hNGFR100E. Negative controls (A,D) are represented by\n cells incubated in absence of hNGF or hNGFR100E. (G) Untreated human\n neuroblastoma SH-SY5Y cells are induced to differentiate when treated\n for 7 days with 100 ng/ml of hNGF (H), or with hNGFR100E (I). The mutant\n hNGFR100E is as effective as wild type hNGF in determining the survival\n and differentiation of chick embryo dorsal root ganglia sensory neurons,\n after a 48 hrs exposure.</p>", "links"=>[], "tags"=>["mutant", "bioactivity", "differentiation", "pc12", "neuroblastoma", "sh-sy5y", "cells", "chick", "drg"], "article_id"=>465149, "categories"=>["Neuroscience"], "users"=>["Simona Capsoni", "Sonia Covaceuszach", "Sara Marinelli", "Marcello Ceci", "Antonietta Bernardo", "Luisa Minghetti", "Gabriele Ugolini", "Flaminia Pavone", "Antonino Cattaneo"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0017321.g002", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_hNGF_mutant_bioactivity_on_survival_and_differentiation_of_PC12____cells_neuroblastoma_SH_SY5Y_cells_and_chick_DRG_neurons_/465149", "title"=>"hNGF mutant bioactivity on survival and differentiation of PC12\n cells, neuroblastoma SH-SY5Y cells and chick DRG neurons.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-02-28 01:25:49"}
  • {"files"=>["https://ndownloader.figshare.com/files/795083"], "description"=>"<p>(A), Experimental scheme of induction of NGF dependence in mouse dorsal\n root ganglia and superior cervical ganglia neurons and hNGF induced\n survival. The mutant hNGFR100E is as effective as wild type hNGF in\n determining the survival and differentiation of mouse (B) dorsal root\n ganglia sensory neurons and (C) superior cervical ganglia, after a 4\n days exposure. hproNGFR100E mutant is less effective than hNGF mutants\n and hproNGF in inducing cells survival in (B) DRGs. (C) hproNGFR100E is\n less effective in the SCG survival test. (D) Cultured rat OPCs express\n only the p75NTR receptor. (E) Expression of the oligodendroccyte\n differentiation marker O4 is reduced in presence of hNGF but not by\n hNGFR100E. (F) Quantification of the percentage of differentiating OPCs\n after exposure to hNGF or hNGFR100E. (G) hproNGF and hproNGFR100E induce\n toxicity in rat OPCs at the dose of 300 ng/ml.</p>", "links"=>[], "tags"=>["mutant", "bioactivity", "ngf", "sympathetic", "sensory", "neurons", "oligodendrocyte", "progenitor", "cells"], "article_id"=>465444, "categories"=>["Neuroscience"], "users"=>["Simona Capsoni", "Sonia Covaceuszach", "Sara Marinelli", "Marcello Ceci", "Antonietta Bernardo", "Luisa Minghetti", "Gabriele Ugolini", "Flaminia Pavone", "Antonino Cattaneo"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0017321.g004", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_hNGF_mutant_bioactivity_on_survival_of_NGF_sympathetic_and_sensory____neurons_and_oligodendrocyte_progenitor_cells_OPCs____differentiation_/465444", "title"=>"hNGF mutant bioactivity on survival of NGF sympathetic and sensory\n neurons and oligodendrocyte progenitor cells (OPCs)\n differentiation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-02-28 01:30:44"}
  • {"files"=>["https://ndownloader.figshare.com/files/794946"], "description"=>"<p>(A) Exposure of human TF1 cells expressing TrkA to hNGF mutants induces a\n similar proliferative response. (B) Experimental scheme of induction of\n NGF dependence in rat hippocampal cells and hNGF induced survival. (C)\n Exposure of rat hippocampal cells to hNGF mutants (HNGFX), for 2 days in\n culture (priming) induces an NGF dependency (cell death after hNGF\n removal, green arm), which is rescued by re-exposing the cells to hNGF\n mutants (blue and red arms). The mutant hNGFR100E is equally effective\n in inducing dependency after priming and survival of rat hippocampal\n neurons (total cell counts). (D-I) Representative fields of experimental\n set-up in B,C. Deprivation of hNGF (E) and of hR100E (H) induces cell\n death caspase -3 activation (in red), compared to neurons exposed to the\n respective hNGF mutants (D,G). Exposure to hNGF (F) and hNGFR100E (I)\n overcomes the cell death induced by anti-NGF addition. Cells were\n counterstained with 4′,6-diamidino-2-phenylindole (DAPI, in\n blue).</p>", "links"=>[], "tags"=>["bioactivity", "tf1", "hippocampal"], "article_id"=>465311, "categories"=>["Neuroscience"], "users"=>["Simona Capsoni", "Sonia Covaceuszach", "Sara Marinelli", "Marcello Ceci", "Antonietta Bernardo", "Luisa Minghetti", "Gabriele Ugolini", "Flaminia Pavone", "Antonino Cattaneo"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0017321.g003", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_hNGFR100E_bioactivity_on_survival_of_TF1_and_hippocampal____neurons_/465311", "title"=>"hNGFR100E bioactivity on survival of TF1 and hippocampal\n neurons.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-02-28 01:28:31"}

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Relative Metric

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