Hereditary Sensory Autonomic Neuropathy type V disorder (HSAN V) is a rare type of autosomal recessive disorder that is clinically characterized by the inability to detect the pain stimuli in adult systems. As a result, patients suffering from this condition do not have the ability to exhibit protective actions against such harmful or life-threatening conditions.
This insensitivity to pain has been attributed to a point mutation of the Nerve Growth Factor (NGF) gene in patients suffering from HSAN V. The mutation impairs the processing and secretion of NGF in adult systems. NGF is a protein that plays a critical role in both developing and mature nervous system. It is an essential component of the pain sensation machinery that exerts trophic actions on cholinergic neurons of the central nervous system. This protein also facilitates the differentiation and development of receptors and functions as an effective sensitizing and inflammatory mediator during physiological and pathological situations. Considering these aforementioned facts, researchers were surprised to discover that patients suffering from HSAN V disorder do not exhibit any form of mental retardation or cognitive impairment. Previous studies have indicated that the mutation of the NGF gene contributes to the reduced secretion of mature NGF. Thus, the clinical phenotype of patients suffering from HSAN V disorder may be due to an alteration in the signaling of the Nerve Growth Factor (NGFR100W) protein or reduced bioavailability of mature NGF protein.
To this effect, Scuola Normale Superiore di Pisa scientists: Dr. Testa Giovanna, Calvello Mariantonietta, Cattaneo Antonino and Professor Simona Capsoni concerted efforts to understand the effect of the reduced bioavailability of mature NGF protein on the clinical phenotype of the homozygous HSAN V condition is caused by. This effect was elucidated by generating and analyzing knock-in mice that contain human NGFR100W alleles. The authors also demonstrated that a central mechanism linked to the NGF-dependent increase of striatal cholinergic neurons contributes to the absence of pain perception in HSAN V patients.
The authors observed that most of the NGFR100W/R100W mice that were born alive with normal size experienced severe weight loss and failed to survive beyond the first month of age. Although the treatment of these mice with wild type NGF restored the bodyweight of the mice, completely reversed their lethal phenotype, and enabled them to survive till the end of the treatment, the increase in body weight of NGFR100W/R100W mice was less than that of the wild type mice.
Furthermore, the researchers discovered that the density of cholinergic neurons increased in the basal forebrain and striatum of NGFR100W/R100W mice while the density of cholinergic neurons in homozygous mice was unaffected in the nucleus basalis and medial septum of Meynert.
Professor Simona Capsoni and her colleagues’ findings show that the postnatal lethal phenotype of homozygous NGFR100W/R100W mice is caused by the systemic NGF haploinsufficiency, which is triggered by the reduced secretion of NGFR100W protein. These findings will serve as an important point of reference for further studies on the interplay between NGF signaling and pain modulation in adult systems. The research work is now published in Biochemical and Biophysical Research Communications.
Testa, G., Calvello, M., Cattaneo, A., and Capsoni, S. Cholinergic Striatal Neurons Are Increased in HSAN V Homozygous Mice despite Reduced NGF Bioavailability, Biochemical and Biophysical Research Communications 509 (2019) 763-766.Go To Biochemical and Biophysical Research Communications 509 (2019)