Nerve growth factor (NGF) is a key mediator of nociception, acting during the development and differentiation of dorsal root ganglion (DRG) neurons, and on adult DRG neuron sensitization to painful stimuli. NGF also has central actions in the brain, where it regulates the phenotypic maintenance of cholinergic neurons. The physiological function of NGF as a pain mediator is altered in patients with Hereditary Sensory and Autonomic Neuropathy type V (HSAN V), caused by the 661C>T transition in the Ngfgene, resulting in the R100W missense mutation in mature NGF. Homozygous HSAN V patients present with congenital pain insensitivity, but are cognitively normal. This led us to hypothesize that the R100W mutation may differentially affect the central and peripheral actions of NGF. To test this hypothesis and provide a mechanistic basis to the HSAN V phenotype, we generated transgenic mice harboring the human 661C>T mutation in the Ngfgene and studied both males and females. We demonstrate that heterozygous NGF(R100W/wt) mice display impaired nociception. DRG neurons of NGF(R100W/wt) mice are morphologically normal, with no alteration in the different DRG subpopulations, whereas skin innervation is reduced. The NGFR(100W) protein has reduced capability to activate pain-specific signaling, paralleling its reduced ability to induce mechanical allodynia. Surprisingly, however, NGF(R100W/wt) mice, unlike heterozygous mNGF(+/-) mice, show no learning or memory deficits, despite a reduction in secretion and brain levels of NGF. The results exclude haploinsufficiency of NGF as a mechanistic cause for heterozygous HSAN V mice and demonstrate a specific effect of the R100W mutation on nociception.

The NGFR100W Mutation Specifically Impairs Nociception without Affecting Cognitive Performance in a Mouse Model of Hereditary Sensory and Autonomic Neuropathy Type V / Testa, Giovanna; Mainardi, Marco; Morelli, Chiara; Olimpico, Francesco; Pancrazi, Laura; Petrella, Carla; Severini, Cinzia; Florio, Rita; Malerba, Francesca; Stefanov, Antonia; Strettoi, Enrica; Brandi, Rossella; Arisi, Ivan; Heppenstall, Paul; Costa, Mario; Capsoni, Simona; Cattaneo, Antonino. - In: THE JOURNAL OF NEUROSCIENCE. - ISSN 0270-6474. - 39:49(2019), pp. 9702-9715. [10.1523/JNEUROSCI.0688-19.2019]

The NGFR100W Mutation Specifically Impairs Nociception without Affecting Cognitive Performance in a Mouse Model of Hereditary Sensory and Autonomic Neuropathy Type V

Testa, Giovanna;Morelli, Chiara;Petrella, Carla;Florio, Rita;Malerba, Francesca;Brandi, Rossella;Costa, Mario;Cattaneo, Antonino
2019

Abstract

Nerve growth factor (NGF) is a key mediator of nociception, acting during the development and differentiation of dorsal root ganglion (DRG) neurons, and on adult DRG neuron sensitization to painful stimuli. NGF also has central actions in the brain, where it regulates the phenotypic maintenance of cholinergic neurons. The physiological function of NGF as a pain mediator is altered in patients with Hereditary Sensory and Autonomic Neuropathy type V (HSAN V), caused by the 661C>T transition in the Ngfgene, resulting in the R100W missense mutation in mature NGF. Homozygous HSAN V patients present with congenital pain insensitivity, but are cognitively normal. This led us to hypothesize that the R100W mutation may differentially affect the central and peripheral actions of NGF. To test this hypothesis and provide a mechanistic basis to the HSAN V phenotype, we generated transgenic mice harboring the human 661C>T mutation in the Ngfgene and studied both males and females. We demonstrate that heterozygous NGF(R100W/wt) mice display impaired nociception. DRG neurons of NGF(R100W/wt) mice are morphologically normal, with no alteration in the different DRG subpopulations, whereas skin innervation is reduced. The NGFR(100W) protein has reduced capability to activate pain-specific signaling, paralleling its reduced ability to induce mechanical allodynia. Surprisingly, however, NGF(R100W/wt) mice, unlike heterozygous mNGF(+/-) mice, show no learning or memory deficits, despite a reduction in secretion and brain levels of NGF. The results exclude haploinsufficiency of NGF as a mechanistic cause for heterozygous HSAN V mice and demonstrate a specific effect of the R100W mutation on nociception.
2019
allodynia; dorsal root ganglia; hereditary sensory and autonomic neuropathy type V; learning and memory; nerve growth factor; skin innervation
01 Pubblicazione su rivista::01a Articolo in rivista
The NGFR100W Mutation Specifically Impairs Nociception without Affecting Cognitive Performance in a Mouse Model of Hereditary Sensory and Autonomic Neuropathy Type V / Testa, Giovanna; Mainardi, Marco; Morelli, Chiara; Olimpico, Francesco; Pancrazi, Laura; Petrella, Carla; Severini, Cinzia; Florio, Rita; Malerba, Francesca; Stefanov, Antonia; Strettoi, Enrica; Brandi, Rossella; Arisi, Ivan; Heppenstall, Paul; Costa, Mario; Capsoni, Simona; Cattaneo, Antonino. - In: THE JOURNAL OF NEUROSCIENCE. - ISSN 0270-6474. - 39:49(2019), pp. 9702-9715. [10.1523/JNEUROSCI.0688-19.2019]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1673171
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