Glaucoma research has traditionally focused on intraocular pressure, axonal injury, and neuroinflammation. A new study in Scientific Reports adds another piece to the picture: altered lipid metabolism within retinal ganglion cells (RGCs).
Researchers at the Eye Research Center in Rochester, Michigan, examined human donor retinas to determine whether glaucoma affects sphingomyelin (SM), a membrane phospholipid involved in cellular organization and stress signaling, and the enzymes responsible for its synthesis and breakdown. Their results suggest that glaucomatous RGCs contain less SM alongside increased activity of acid sphingomyelinase (ASM), an enzyme that converts SM into ceramide.
The team analyzed fixed and flash-frozen retinal tissue from donors with and without a glaucoma diagnosis. RGCs were identified using RBPMS labeling, while SM was detected with EGFP-Lysenin, a probe that selectively binds the lipid. The investigators also assessed ASM and neutral sphingomyelinase (NSM), as well as the SM-synthesizing enzymes SMS1 and SMS2.
As expected, RGC density was significantly lower in glaucoma donor retinas. More intriguingly, SM labeling was also significantly reduced in surviving RGCs. The difference was evident at the individual-cell level and was independently confirmed in flash-frozen retinal homogenates. The study authors argue that this finding suggests SM depletion may occur before complete RGC loss rather than simply reflecting fewer surviving neurons.
The researchers then investigated what might be driving that depletion. ASM expression was significantly higher in the RGC layer and within individual RGCs from glaucomatous eyes. By contrast, glaucoma was not associated with significant changes in NSM, SMS1, or SMS2, suggesting that the reduction in SM was more likely related to increased degradation than impaired synthesis.
Ceramide offered another clue. Total RGC ceramide levels were not significantly different between groups, but glaucomatous eyes contained significantly more ceramide aggregates within RGCs. The study authors propose that localized ASM-mediated SM breakdown could promote formation of ceramide-rich membrane platforms capable of amplifying pro-apoptotic signaling.
The work remains exploratory. The number of human donor samples was small, medical histories were incomplete, and causes of death were not balanced between groups. Sepsis, in particular, was more common among glaucoma donors and represents a potential confounder. Although the authors argue that the specific ASM activity pattern observed makes it unlikely to fully explain the findings, and note that the subsample contained only one donor who had died due to sepsis.
Despite those limitations, the study provides direct human evidence that the ASM–sphingomyelin–ceramide pathway is disrupted in glaucoma. Combined with earlier animal data showing that reduced ASM expression can protect RGCs after IOP elevation, the findings raise ASM inhibition as a possible future neuroprotective strategy – and lipid metabolism as another avenue through which glaucoma may ultimately be understood and treated.
