| First Author | Akiyama H | Year | 2020 |
| Journal | J Biol Chem | Volume | 295 |
| Issue | 16 | Pages | 5257-5277 |
| PubMed ID | 32144204 | Mgi Jnum | J:286824 |
| Mgi Id | MGI:6404682 | Doi | 10.1074/jbc.RA119.012502 |
| Citation | Akiyama H, et al. (2020) Glucocerebrosidases catalyze a transgalactosylation reaction that yields a newly-identified brain sterol metabolite, galactosylated cholesterol. J Biol Chem 295(16):5257-5277 |
| abstractText | beta-Glucocerebrosidase (GBA) hydrolyzes glucosylceramide (GlcCer) to generate ceramide. Previously, we demonstrated that lysosomal GBA1 and nonlysosomal GBA2 possess not only GlcCer hydrolase activity, but also transglucosylation activity to transfer the glucose residue from GlcCer to cholesterol to form beta-cholesterylglucoside (beta-GlcChol) in vitro beta-GlcChol is a member of sterylglycosides present in diverse species. How GBA1 and GBA2 mediate beta-GlcChol metabolism in the brain is unknown. Here, we purified and characterized sterylglycosides from rodent and fish brains. Although glucose is thought to be the sole carbohydrate component of sterylglycosides in vertebrates, structural analysis of rat brain sterylglycosides revealed the presence of galactosylated cholesterol (beta-GalChol), in addition to beta-GlcChol. Analyses of brain tissues from GBA2-deficient mice and GBA1- and/or GBA2-deficient Japanese rice fish (Oryzias latipes) revealed that GBA1 and GBA2 are responsible for beta-GlcChol degradation and formation, respectively, and that both GBA1 and GBA2 are responsible for beta-GalChol formation. Liquid chromatography-tandem MS revealed that beta-GlcChol and beta-GalChol are present throughout development from embryo to adult in the mouse brain. We found that beta-GalChol expression depends on galactosylceramide (GalCer), and developmental onset of beta-GalChol biosynthesis appeared to be during myelination. We also found that beta-GlcChol and beta-GalChol are secreted from neurons and glial cells in association with exosomes. In vitro enzyme assays confirmed that GBA1 and GBA2 have transgalactosylation activity to transfer the galactose residue from GalCer to cholesterol to form beta-GalChol. This is the first report of the existence of beta-GalChol in vertebrates and how beta-GlcChol and beta-GalChol are formed in the brain. |
