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Papers of the Week


Papers: 9 Nov 2019 - 15 Nov 2019


Animal Studies


2019 Dec 04


J Neurosci


39


49

The NGF mutation specifically impairs nociception without affecting cognitive performance in a mouse model of Hereditary Sensory and Autonomic Neuropathy type V.

Authors

Testa G, Mainardi M, Morelli C, Olimpico F, Pancrazi L, Petrella C, Severini C, Florio R, Malerba F, Stefanov A, Strettoi E, Brandi R, Arisi I, Heppenstall P, Costa M, Capsoni S, Cattaneo A
J Neurosci. 2019 Dec 04; 39(49):9702-9715.
PMID: 31685654.

Abstract

Nerve Growth Factor (NGF) is a key mediator of nociception, acting during development and differentiation of dorsal root ganglia (DRGs) neurons, and on adult DRG neuron sensitization to painful stimuli. NGF has also 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 V (HSAN V), caused by the 661C>T transition in the 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 harbouring the human 661C>T mutation in the gene, and studied both males and females. We demonstrate that heterozygous NGF mice display impaired nociception. DRG neurons of NGF mice are morphologically normal, with no alteration in the different DRG subpopulations, whereas skin innervation is reduced. The NGF protein has reduced capability to activate pain-specific signalling, paralleling its reduced ability to induce mechanical allodynia. Surprisingly, however, NGF mice, unlike heterozygous mNGF mice, show no learning nor 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 R100W mutation in Nerve Growth Factor (NGF) causes Hereditary Sensory and Autonomic Neuropathy type V (HSAN 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). Mutant mice have normal nociceptor populations which, however, display decreased activation of pain transduction pathways. NGF interferes with peripheral and central NGF bioavailability, but this does not impact on central nervous system function, as demonstrated by normal learning and memory, in contrast with heterozygous NGF knock-out mice. Thus, a point mutation allows to split neurotrophic and pronociceptive functions of NGF, with interesting implications for treatment of chronic pain.