The NGF R100W Mutation Specifically Impairs Nociception without Affecting Cognitive Performance in a Mouse Model of Hereditary Sensory and Autonomic Neuropathy Type V.

Autor:	Testa G; Bio@SNS, Scuola Normale Superiore, 56124 Pisa, Italy., Mainardi M; Bio@SNS, Scuola Normale Superiore, 56124 Pisa, Italy., Morelli C; European Molecular Biology Laboratory (EMBL), 00015 Monterotondo (Rome), Italy.; EMBL International PhD Programme, Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany., Olimpico F; Bio@SNS, Scuola Normale Superiore, 56124 Pisa, Italy., Pancrazi L; Bio@SNS, Scuola Normale Superiore, 56124 Pisa, Italy.; Institute of Neuroscience, National Research Council (CNR), 56124 Pisa, Italy., Petrella C; Institute of Biochemistry and Cell Biology (IBBC), CNR, DOS Policlinico Umberto I, 00161 Rome, Italy., Severini C; Institute of Biochemistry and Cell Biology (IBBC), CNR, DOS Policlinico Umberto I, 00161 Rome, Italy., Florio R; Neurotrophins and Neurodegenerative Diseases Laboratory, Rita Levi-Montalcini European Brain Research Institute (EBRI), 00161 Rome, Italy, and., Malerba F; Neurotrophins and Neurodegenerative Diseases Laboratory, Rita Levi-Montalcini European Brain Research Institute (EBRI), 00161 Rome, Italy, and., Stefanov A; Institute of Neuroscience, National Research Council (CNR), 56124 Pisa, Italy., Strettoi E; Institute of Neuroscience, National Research Council (CNR), 56124 Pisa, Italy., Brandi R; Neurotrophins and Neurodegenerative Diseases Laboratory, Rita Levi-Montalcini European Brain Research Institute (EBRI), 00161 Rome, Italy, and., Arisi I; Neurotrophins and Neurodegenerative Diseases Laboratory, Rita Levi-Montalcini European Brain Research Institute (EBRI), 00161 Rome, Italy, and., Heppenstall P; European Molecular Biology Laboratory (EMBL), 00015 Monterotondo (Rome), Italy., Costa M; Institute of Neuroscience, National Research Council (CNR), 56124 Pisa, Italy., Capsoni S; Bio@SNS, Scuola Normale Superiore, 56124 Pisa, Italy, antonino.cattaneo@sns.it simona.capsoni@sns.it.; Institute of Physiology, Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, 44121 Ferrara, Italy., Cattaneo A; Bio@SNS, Scuola Normale Superiore, 56124 Pisa, Italy, antonino.cattaneo@sns.it simona.capsoni@sns.it.; Neurotrophins and Neurodegenerative Diseases Laboratory, Rita Levi-Montalcini European Brain Research Institute (EBRI), 00161 Rome, Italy, and.
Jazyk:	angličtina
Zdroj:	The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2019 Dec 04; Vol. 39 (49), pp. 9702-9715. Date of Electronic Publication: 2019 Nov 04.
DOI:	10.1523/JNEUROSCI.0688-19.2019
Abstrakt:	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 Ngf gene, 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 Ngf gene 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 NGF R100W 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. SIGNIFICANCE STATEMENT The R100W mutation in nerve growth factor (NGF) causes Hereditary Sensory and Autonomic Neuropathy type V, a rare disease characterized by impaired nociception, even in apparently clinically silent heterozygotes. For the first time, we generated and characterized heterozygous knock-in mice carrying the human R100W-mutated allele (NGF R100W/wt ). Mutant mice have normal nociceptor populations, which, however, display decreased activation of pain transduction pathways. NGF R100W interferes with peripheral and central NGF bioavailability, but this does not impact on CNS function, as demonstrated by normal learning and memory, in contrast with heterozygous NGF knock-out mice. Thus, a point mutation allows neurotrophic and pronociceptive functions of NGF to be split, with interesting implications for the treatment of chronic pain. (Copyright © 2019 the authors.)
Databáze:	MEDLINE
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