Sex-dependent differences and age-dependent regulation of the ASIC1a–ERK pathway in a mouse model of Fabry disease

Fabry disease (FD) is characterized by early pain manifestations and well-recognized sex differences in clinical presentation, yet the molecular basis underlying these differences remains poorly understood. We previously demonstrated increased ASIC1a expression and ERK activation in pain-related structures of GlaKO mice at 4 and 8 months of age. Here, we extended these studies to determine how ASIC1a–ERK signaling changes across early and adult stages and whether these changes differ between males and females. ASIC1a and phosphorylated ERK (pERK) expression were evaluated in male and female GlaKO mice at 2, 4, and 8 months of age. ASIC1a and pERK levels in dorsal root ganglia (DRG) and spinal cord, representing peripheral and central nervous system tissues, respectively, remained largely unchanged between 2 and 4 months but increased at 8 months in both sexes. Across ages, females consistently exhibited higher ASIC1a and pERK levels than males, already evident at 2 months, before sexual maturation. Similar sex-dependent differences were observed in the cerebral cortex, where female GlaKO mice showed higher ASIC1a and pERK expression than males across the ages examined. Together, these results provide new insight into the temporal and sex-dependent regulation of ASIC1a–ERK signaling in FD and support further investigation of this pathway as a potential contributor to sex-related differences in Fabry-associated pain.