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Akiyama, H.; Ide, M.; Nagatsuka, Y.; Sayano, T.; Nakanishi, E.; Uemura, N.; ... ; Hirabayashi, Y. (2020)

Glucocerebrosidases catalyze a transgalactosylation reaction that yields a newly-identified brain sterol metabolite, galactosylated cholesterol

Article / Letter to editor
?-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 ?-cholesterylglucoside (?-GlcChol) in vitro. ?-GlcChol is a member of sterylglycosides present in diverse species. How GBA1 and GBA2 mediate ?-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 (?-GalChol), in addition to ?-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 ?-GlcChol...Show more?-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 ?-cholesterylglucoside (?-GlcChol) in vitro. ?-GlcChol is a member of sterylglycosides present in diverse species. How GBA1 and GBA2 mediate ?-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 (?-GalChol), in addition to ?-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 ?-GlcChol degradation and formation, respectively, and that both GBA1 and GBA2 are responsible for ?-GalChol formation. Liquid chromatography?tandem MS revealed that ?-GlcChol and ?-GalChol are present throughout development from embryo to adult in the mouse brain. We found that ?-GalChol expression depends on galactosylceramide (GalCer), and developmental onset of ?-GalChol biosynthesis appeared to be during myelination. We also found that ?-GlcChol and ?-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 ?-GalChol. This is the first report of the existence of ?-GalChol in vertebrates and how ?-GlcChol and ?-GalChol are formed in the brain.Show less
All authors
Akiyama, H.; Ide, M.; Nagatsuka, Y.; Sayano, T.; Nakanishi, E.; Uemura, N.; Yuyama, K.; Yamaguchi, Y.; Kamiguchi, H.; Takahashi, R.; Aerts, J.M.F.G.; Greimel, P.; Hirabayashi, Y.
Date
2020-04-17
Journal
Journal of Biological Chemistry
Volume
295
Issue
16
Pages
5257 - 5277
DOI
doi:10.1074/jbc.RA119.012502