Neurobiol Dis. 2026 Sep 4;229:107595. doi: 10.1016/j.nbd.2026.107595. Online ahead of print.
ABSTRACT
Fabry disease (FD) is a genetic disorder caused by a deficiency of alpha-galactosidase A. Neuropathic pain is a hallmark of FD, beginning in early childhood and persisting throughout life. Current therapies for FD, such as enzyme replacement therapy and oral chaperone therapy, have limited impact on alleviating pain symptoms. Therefore, there is an urgent need to elucidate the precise molecular and metabolic mechanisms underlying FD-related pain to identify new therapeutic targets. In this study, we found that 8-week-old Fabry mice exhibited pronounced pain hypersensitivity, with no sex differences. Then, bilateral L4-L6 dorsal root ganglia (DRGs) were harvested from Fabry and wild-type (WT) mice of both sexes to dissect the molecular basis of pain. Transcriptomic profiling revealed distinct alterations in lipid metabolism-related genes within Fabry DRGs. Subsequent targeted lipidomic analysis identified robust accumulation of phosphatidylglycerol (PG), particularly elevated levels of PG (18:1/22:6) and PG (18:2/22:6) in Fabry DRGs. PG-associated synthase PGS1 was upregulated, while the PG hydrolytic activity of sPLA2s was inhibited. Following PGS1 knockdown or sPLA2s activity restoration, PG accumulation and pain hypersensitivity in Fabry mice were mitigated. Given the mitochondrial localization of PGS1, we observed profound mitochondrial disruption in Fabry DRGs, where aberrant PG metabolism contributes to this dysfunction. Thus, our study provides new insights into DRG pathogenesis in FD and uncovers dysregulated PG metabolism as a promising therapeutic target for alleviating Fabry pain.
PMID:42697517 | DOI:10.1016/j.nbd.2026.107595