Abstract Text: Ether phospholipids are unique glycerophospholipids that contain an ether bond at the sn-1 position of their glycerol backbone. They play crucial roles in membrane raft formation, membrane trafficking and cell signaling, and provide protection to the membrane structure against oxidative stress. Almost 20% of brain lipids are consist of ether phospholipids. Their deficiency has been implicated in different neurodegenerative diseases. However, how ether phospholipids are regulated after traumatic brain injury (TBI) is not clearly known. In this study, we determined the levels of ether phospholipids in the cortices of sham and TBI mice using liquid chromatography tandem mass spectrometry (LC-MS/MS) based lipidomic analysis. Our data showed a significant decrease in ether phospholipid abundance in the injured mouse cortices following controlled cortical impact (CCI) induced TBI as compared to the sham mice. This is most likely due to the dysregulation in ether phospholipid synthesis in the brain following TBI. Peroxisome, a single membrane bound organelle, serves as the site for the initiation of ether phospholipids synthesis. Peroxisomal enzymes fatty acyl-CoA reductase 1 and 2 (FAR1/2), glyceronephosphate O-acyltransferase (GNPAT) and alkylglycerone phosphate synthase (AGPS) are involved in generating ether phospholipid precursors, which are transported to the endoplasmic reticulum for the completion of ether phospholipid synthesis. We detected marked decrease in FAR1 and GNPAT levels in the injured cortices of TBI mice indicating impairment in peroxisomal ether phospholipid synthesis following TBI. In order to restore ether phospholipid level in the injured brain, we fed TBI mice an ether phospholipid precursor – 1-O-octadecylglycerol (OAG). The levels of several ether phospholipids in the injured cortices of mice fed with OAG were restored to those of sham mice at day 28 after TBI. We also observed functional improvement in these mice as compared to the untreated injured mice. Taken together, our data demonstrate that peroxisomal ether phospholipid synthesis is disrupted in the cortices following brain injury, which contributes to the functional impairment after TBI.
