Human TrkA(R649W) mutation impairs nociception, sweating and cognitive abilities: a mouse model of HSAN IV
A functional nerve growth factor NGF–Tropomyosin Receptor kinase A (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, na...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10077510/ https://www.ncbi.nlm.nih.gov/pubmed/36537577 http://dx.doi.org/10.1093/hmg/ddac295 |
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author | Pacifico, Paola Testa, Giovanna Amodeo, Rosy Mainardi, Marco Tiberi, Alexia Convertino, Domenica Arevalo, Juan Carlos Marchetti, Laura Costa, Mario Cattaneo, Antonino Capsoni, Simona |
author_facet | Pacifico, Paola Testa, Giovanna Amodeo, Rosy Mainardi, Marco Tiberi, Alexia Convertino, Domenica Arevalo, Juan Carlos Marchetti, Laura Costa, Mario Cattaneo, Antonino Capsoni, Simona |
author_sort | Pacifico, Paola |
collection | PubMed |
description | A functional nerve growth factor NGF–Tropomyosin Receptor kinase A (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–TrkA 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 TrkA(R649W) 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, TrkA(R649W/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 TrkA(h/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–TrkA system in pain sensation. |
format | Online Article Text |
id | pubmed-10077510 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-100775102023-04-07 Human TrkA(R649W) mutation impairs nociception, sweating and cognitive abilities: a mouse model of HSAN IV Pacifico, Paola Testa, Giovanna Amodeo, Rosy Mainardi, Marco Tiberi, Alexia Convertino, Domenica Arevalo, Juan Carlos Marchetti, Laura Costa, Mario Cattaneo, Antonino Capsoni, Simona Hum Mol Genet Original Article A functional nerve growth factor NGF–Tropomyosin Receptor kinase A (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–TrkA 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 TrkA(R649W) 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, TrkA(R649W/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 TrkA(h/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–TrkA system in pain sensation. Oxford University Press 2022-12-20 /pmc/articles/PMC10077510/ /pubmed/36537577 http://dx.doi.org/10.1093/hmg/ddac295 Text en © The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Original Article Pacifico, Paola Testa, Giovanna Amodeo, Rosy Mainardi, Marco Tiberi, Alexia Convertino, Domenica Arevalo, Juan Carlos Marchetti, Laura Costa, Mario Cattaneo, Antonino Capsoni, Simona Human TrkA(R649W) mutation impairs nociception, sweating and cognitive abilities: a mouse model of HSAN IV |
title | Human TrkA(R649W) mutation impairs nociception, sweating and cognitive abilities: a mouse model of HSAN IV |
title_full | Human TrkA(R649W) mutation impairs nociception, sweating and cognitive abilities: a mouse model of HSAN IV |
title_fullStr | Human TrkA(R649W) mutation impairs nociception, sweating and cognitive abilities: a mouse model of HSAN IV |
title_full_unstemmed | Human TrkA(R649W) mutation impairs nociception, sweating and cognitive abilities: a mouse model of HSAN IV |
title_short | Human TrkA(R649W) mutation impairs nociception, sweating and cognitive abilities: a mouse model of HSAN IV |
title_sort | human trka(r649w) mutation impairs nociception, sweating and cognitive abilities: a mouse model of hsan iv |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10077510/ https://www.ncbi.nlm.nih.gov/pubmed/36537577 http://dx.doi.org/10.1093/hmg/ddac295 |
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