Phospholipid Interconversion and Transport Are Altered in Glaucoma

Glaucoma, the leading cause of irreversible blindness worldwide, is characterized by elevated intraocular pressure (IOP) resulting from impaired aqueous humor (AH) outflow through the trabecular meshwork (TM). We demonstrate altered phospholipids (PLs) levels and increased activity of the interconversion enzyme phosphatidylserine decarboxylase (PSD) in the TM of individuals with primary open-angle glaucoma. Elevating PSD alone is sufficient to raise IOP in normotensive mice, whereas depleting PSD restores IOP in glaucomatous mice. Although certain PL classes are generally altered in glaucoma, specific PLs with minor structural variations within those classes exhibit variability in their levels in TM and AH, indicating a potential lipid transport abnormality. We identified a distinct set of ocular lipid species altered in glaucoma, implicating alterations in the levels and functionality of the lipid transporter ATP8B2. This flippase alone, however, does not seem to affect IOP but appears to amplify the effects of PSD.