ASIC1a-associated mechanical hypersensitivity in the GlaKO Fabry disease mouse model

Abstract

Different lines of evidence point to a role for Acid-sensing ion channel 1 (ASIC1) in pain perception, acting as sensors in both the central nervous system and peripheral tissues. While elevated ASIC1 protein expression has been documented in various pain conditions, our study focuses on its involvement in the context of Fabry disease (FD).

Using a mouse model of FD, we observed a significant increase in ASIC1 protein expression in pain-related areas including the anterior cingulate cortex (ACC), as well as the spinal cord (SC) and dorsal root ganglia (DRG) at the lumbar, thoracic, and cervical levels. This upregulation was accompanied by increased ASIC1a mRNA levels and ERK phosphorylation. Moreover, in FD mice, ASIC1 protein expression was found to be modulated by age and sex: it was higher in female mice than in males, and increased with age in both sexes.

These findings, together with our previous work showing unaltered ASIC1a mRNA levels but microRNA-mediated regulation of ASIC1a protein in the formalin-induced acute pain model, highlight distinct mechanisms of ASIC1a regulation in FD-associated versus acute pain. Additionally, our study revealed heightened mechanical sensitivity in FD mice that could be prevented using a channel blocker, further highlighting the involvement of ASIC1a channels in pain pathways associated with Fabry disease. Our findings suggest that ASIC1a channels may serve as promising therapeutic targets for pain management in Fabry disease.