{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T11:06:20Z","timestamp":1770462380826,"version":"3.49.0"},"reference-count":105,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2022,12,20]],"date-time":"2022-12-20T00:00:00Z","timestamp":1671494400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"MIUR_PRIN17 project","award":["2017HPTFFC_001"],"award-info":[{"award-number":["2017HPTFFC_001"]}]},{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","award":["GGP11179"],"award-info":[{"award-number":["GGP11179"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","award":["603191"],"award-info":[{"award-number":["603191"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,4,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>A functional nerve growth factor NGF\u2013Tropomyosin Receptor kinase A\u00a0(TrkA) system is an essential requisite for the generation and maintenance of long-lasting thermal and mechanical hyperalgesia in adult mammals. Indeed, mutations in the gene encoding for TrkA are responsible for a rare condition, named Hereditary Sensory and Autonomic Neuropathy type IV (HSAN IV), characterized by the loss of response to noxious stimuli, anhidrosis and cognitive impairment. However, to date, there is no available mouse model to properly understand how the NGF\u2013TrkA system can lead to pathological phenotypes that are distinctive of HSAN IV. Here, we report the generation of a knock-in mouse line carrying the HSAN IV TrkAR649W mutation. First, by in vitro biochemical and biophysical analyses, we show that the pathological R649W mutation leads to kinase-inactive TrkA also affecting its membrane dynamics and trafficking. In agreement with the HSAN IV human phenotype, TrkAR649W\/m mice display a lower response to thermal and chemical noxious stimuli, correlating with reduced skin innervation, in addition to decreased sweating in comparison to TrkAh\/m controls. Moreover, the R649W mutation decreases anxiety-like behavior and compromises cognitive abilities, by impairing spatial-working and social memory. Our results further uncover unexplored roles of TrkA in thermoregulation and sociability. In addition to accurately recapitulating the clinical manifestations of HSAN IV patients, our findings contribute to clarifying the involvement of the NGF\u2013TrkA system in pain sensation.<\/jats:p>","DOI":"10.1093\/hmg\/ddac295","type":"journal-article","created":{"date-parts":[[2022,12,20]],"date-time":"2022-12-20T16:25:49Z","timestamp":1671553549000},"page":"1380-1400","source":"Crossref","is-referenced-by-count":6,"title":["Human TrkAR649W mutation impairs nociception, sweating and cognitive abilities: a mouse model of HSAN IV"],"prefix":"10.1093","volume":"32","author":[{"given":"Paola","family":"Pacifico","sequence":"first","affiliation":[{"name":"Scuola Normale Superiore Bio@SNS Laboratory, , Pisa 56124 , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanna","family":"Testa","sequence":"additional","affiliation":[{"name":"Scuola Normale Superiore Bio@SNS Laboratory, , Pisa 56124 , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosy","family":"Amodeo","sequence":"additional","affiliation":[{"name":"Center for Nanotechnology Innovation @NEST, Istituto Italiano di Tecnologia , Pisa 56127 , Italy"},{"name":"Scuola Normale Superiore NEST, , Pisa 56127 , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Mainardi","sequence":"additional","affiliation":[{"name":"Scuola Normale Superiore Bio@SNS Laboratory, , Pisa 56124 , Italy"},{"name":"Neuroscience Institute, National Research Council (IN-CNR) , Pisa 56124 , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexia","family":"Tiberi","sequence":"additional","affiliation":[{"name":"Scuola Normale Superiore Bio@SNS Laboratory, , Pisa 56124 , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Domenica","family":"Convertino","sequence":"additional","affiliation":[{"name":"Center for Nanotechnology Innovation @NEST, Istituto Italiano di Tecnologia , Pisa 56127 , Italy"},{"name":"Scuola Normale Superiore NEST, , Pisa 56127 , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan Carlos","family":"Arevalo","sequence":"additional","affiliation":[{"name":"Instituto de Neurociencias de Castilla y Le\u00f3n, University of Salamanca Departmento de Biolog\u00eda Celular y Patolog\u00eda, , Salamanca 37007 , Spain"},{"name":"Institute of Biomedical Research of Salamanca , Salamanca 37007 , Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Marchetti","sequence":"additional","affiliation":[{"name":"Center for Nanotechnology Innovation @NEST, Istituto Italiano di Tecnologia , Pisa 56127 , Italy"},{"name":"University of Pisa Department of Pharmacy, , Pisa 56126 , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mario","family":"Costa","sequence":"additional","affiliation":[{"name":"Neuroscience Institute, National Research Council (IN-CNR) , Pisa 56124 , Italy"},{"name":"Pisa Center for Research and Clinical Implementation Flash Radiotherapy (CPFR@CISUP) , Pisa 56126 , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonino","family":"Cattaneo","sequence":"additional","affiliation":[{"name":"Scuola Normale Superiore Bio@SNS Laboratory, , Pisa 56124 , Italy"},{"name":"Rita Levi-Montalcini European Brain Research Institute (EBRI) , Rome 00161 , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2670-8237","authenticated-orcid":false,"given":"Simona","family":"Capsoni","sequence":"additional","affiliation":[{"name":"Scuola Normale Superiore Bio@SNS Laboratory, , Pisa 56124 , Italy"},{"name":"Institute of Physiology, University of Ferrara Department of Neuroscience and Rehabilitation, , Ferrara 44121 , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2022,12,20]]},"reference":[{"key":"2023040610563359400_","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1098\/rstb.1996.0039","article-title":"NGF as a mediator of inflammatory pain","volume":"351","author":"McMahon","year":"1996","journal-title":"Phil. 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