Swedish Nerve Growth Factor Mutation (NGF^R100W) Defines a Role for TrkA and p75^NTRin Nociception

Abstract

Nerve growth factor (NGF) exerts multiple functions on target neurons throughout development. The recent discovery of a point mutation leading to a change from arginine to tryptophan at residue 100 in the mature NGFβ sequence (NGF) in patients with hereditary sensory and autonomic neuropathy type V (HSAN V) made it possible to distinguish the signaling mechanisms that lead to two functionally different outcomes of NGF: trophic versus nociceptive. We performed extensive biochemical, cellular, and live-imaging experiments to examine the binding and signaling properties of NGF Our results show that, similar to the wild-type NGF (wtNGF), the naturally occurring NGF mutant was capable of binding to and activating the TrkA receptor and its downstream signaling pathways to support neuronal survival and differentiation. However, NGF failed to bind and stimulate the 75 kDa neurotrophic factor receptor (p75)-mediated signaling cascades (i.e., the RhoA-Cofilin pathway). Intraplantar injection of NGF into adult rats induced neither TrkA-mediated thermal nor mechanical acute hyperalgesia, but retained the ability to induce chronic hyperalgesia based on agonism for TrkA signaling. Together, our studies provide evidence that NGF retains trophic support capability through TrkA and one aspect of its nociceptive signaling, but fails to engage p75 signaling pathways. Our findings suggest that wtNGF acts via TrkA to regulate the delayed priming of nociceptive responses. The integration of both TrkA and p75 signaling thus appears to regulate neuroplastic effects of NGF in peripheral nociception. In the present study, we characterized the naturally occurring nerve growth factor NGF mutant that is associated with hereditary sensory and autonomic neuropathy type V. We have demonstrated for the first time that NGF retains trophic support capability through TrkA, but fails to engage p75 signaling pathways. Furthermore, after intraplantar injection into adult rats, NGF induced neither thermal nor mechanical acute hyperalgesia, but retained the ability to induce chronic hyperalgesia. We have also provided evidence that the integration of both TrkA- and p75-mediated signaling appears to regulate neuroplastic effects of NGF in peripheral nociception. Our study with NGF suggests that it is possible to uncouple trophic effect from nociceptive function, both induced by wild-type NGF.

A congenital pain insensitivity mutation in the nerve growth factor gene uncouples nociception from affective pain in heterozygous humans and mice

“…Thus, hNGF R100W protein displays an indistinguishable neurotrophic potency from wild type hNGF, while showing a reduced ability to sensitize sensory neurons. This extends data showing that hNGF R100W uncouples trophic effects from nociceptive functions of NGF [10][11][12] .…”

Targeted Mutation (R100W) of the Gene Encoding NGF Leads to Deficits in the Peripheral Sensory Nervous System

“…Further studies demonstrated that R100W mutation did not affect NGF binding to TrkA, while it abolished NGF binding to p75 NTR ( Capsoni et al, 2011 ). Our previous study also demonstrated that NGF R100W maintained the ability of binding to and activating the TrkA to support neuronal survival and differentiation ( Sung et al, 2018 ), which could explain why the cognitive impairment of HSAN V patients appeared very limited or absent.…”

“…Previous research on NGF R100W revealed that R100W mutation selectively disrupted binding of NGF to p75 NTR , while it retained the ability of binding to TrkA ( Covaceuszach et al, 2010 ; Sung et al, 2018 ). The p75 NTR is transiently synthesized in embryonic kidney ( Sariola et al, 1991 ).…”

“…HSAN V patients appear to suffer from loss of pain sensation, but without overt mental retardation, suggesting that the NGF R100W mutation may selectively cause loss of pain function while retaining its trophic function. In a previous study, we already demonstrated that NGF R100W maintained the ability of binding to and activating the TrkA to support neuronal survival and differentiation, but failed to bind and engage p75 NTR signaling pathways ( Sung et al, 2018 ).…”

Unveiling functional motions based on point mutations in biased signaling systems: A normal mode study on Nerve Growth Factor bound to TrkA

“…However, these motions are not capable of fully activating the biased TrkA signaling, since the R221W mutation inhibits the PLC-γ1 pathway [34], permanently impairing the nociceptive response [33,34,36,37]. Therefore, WT NGF presents a second mechanism to activate the nociception downstream promoted by TrkA, while R221W structures has this mechanism knocked-down as recently raised [57]. Here, we describe the collective motions putatively linked to nociceptive response of TrkA receptors and showed that R221W complex is not capable to reproduce these motions even when the WT motions were forced to the mutant structures.…”