Human TrkAR649W mutation impairs nociception, sweating and cognitive abilities: a mouse model of HSAN IV

Abstract

A functional nerve growth factor (NGF)–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 TrkAR649W 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, TrkAR649W/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 TrkAh/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 clarify the involvement of the NGF–TrkA system in pain sensation.

Peripheral mechanisms of peripheral neuropathic pain

“…Loss of function mutations in TrkA have been found in HSAN IV affected individuals, leading to pain insensitivity, anhidrosis and intellectual disability ( Indo, 2018 ). As observed in the humanized knock-in animal model of HSAN IV carrying the TrkA R649W mutation, alterations in the phosphorylation state and membrane dynamics of TrkA result in a reduced pain sensation and compromised thermoregulation ( Pacifico et al, 2023 ). These results suggest that the development of small molecules which reduce TrkA kinase activity could represent feasible analgesics candidates for pain treatment.…”