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Fabry disease-associated globotriaosylceramide induces mechanical allodynia via activation of signaling through proNGF-p75NTR but not mature NGF-TrkA.

Abstract：

:Fabry disease (FD) is an X-linked metabolic storage disorder arising from the deficiency of lysosomal α-galactosidase A, which leads to the gradual accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3), throughout the body. Pain in the extremities is an early symptom of FD; however, the underlying pathophysiological mechanisms remain unknown. α-Galactosidase A knockout animals exhibit nociceptive behaviors, with enhanced expression levels of several ion channels. These characteristics are observed in animals treated with nerve growth factor (NGF). Here, we aimed to elucidate the potential of NGF signaling as a cause of FD-associated pain, using intraplantar Gb3-treated mice displaying mechanical allodynia. Treatment with a neutralizing antibody against a precursor of NGF (proNGF) or its receptor, p75 neurotrophin receptor (p75NTR), resulted in the recovery from Gb3-induced pain. Conversely, anti-NGF and anti-tropomyosin receptor kinase A antibodies failed to exert analgesic effects. Gb3 injection had no effects on the expression levels of proNGF and p75NTR in the plantar skin and dorsal root ganglia, suggesting that Gb3 activates the pain pathway, possibly mediated through functional up-regulation of proNGF-p75NTR signaling. Furthermore, by pharmacological approaches using a protein kinase A (PKA) inhibitor and a cholesterol-removing agent, we found that p75NTR-phosphorylating PKA and lipid rafts for phosphorylated p75NTR translocation were required for Gb3-induced pain. These results suggest that acute exposure to Gb3 induces mechanical allodynia via activation of the proNGF-p75NTR pathway, which involves lipid rafts and PKA. Our findings provide new pathological insights into FD-associated pain, and suggest the need to develop therapeutic interventions targeting proNGF-p75NTR signaling.

journal_name

Eur J Pharmacol

journal_title

European journal of pharmacology

authors

Sugimoto J,Satoyoshi H,Takahata K,Muraoka S

doi

10.1016/j.ejphar.2021.173882

subject

Has Abstract

pub_date

2021-01-20 00:00:00

pages

173882

eissn

0014-2999

issn

1879-0712

pii

S0014-2999(21)00035-2

journal_volume

895

pub_type

杂志文章

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Fabry disease-associated globotriaosylceramide induces mechanical allodynia via activation of signaling through proNGF-p75NTR but not mature NGF-TrkA.