Abstract
Beta (β)-glucosidase 2 (GBA2) is deficient in a form of human spastic paraplegia due to defects in GBA2 (SPG46). GBA2 was proposed as a modifier of Gaucher disease, a lysosomal storage disease resulting from deficient β-glucosidase 1; GBA1. Current GBA2 activity assays using artificial substrates incompletely model the activity encountered in vivo. We studied GBA2 activity, using lithocholic acid β-glucoside or glucosylceramide as natural β-glucosidase substrates in murine tissues or cultured patient fibroblasts with the pathologic genotypes: Gba1−/−; Gba2−/−; GBA1−/−; GBA2+/− and found expected and unexpected deviations from normal controls.
Acknowledgments
Dr. Rebecca Schüle-Freyer, Dr. Ulrike Ulmer, Mrs. Jennifer Reichbauer, all from Centre for Neurology, Hertie Institute for Clinical Brain Research and German Centre of Neurodegenerative Diseases (DZNE), Eberhard-Karls-University Tübingen, Germany, are sincerely thanked for having provided the cell lines from the SPG46-heterozygotes GBA2+/−, for their advice and help with cell culturing. Dr. Ellen Sidransky, Medical Genetics Branch NIH, Bethesda, USA, is thanked for the tissues and fibroblasts from the Gba1−/− mouse.
References
Aureli, M., Samarani, M., Loberto, N., Mancini, G., Murdica, V., Chiricozzi, E., Prinetti, A., Bassi, R., and Sonnino, S. (2016). Current and novel aspects on the non-lysosomal β-glucosylceramidase GBA2. Neurochem. Res. 41, 210–220.10.1007/s11064-016-1833-0Search in Google Scholar PubMed
Ben Bdira, F., Artola, M., Overkleeft, H.S., Ubbink, M., and Aerts, J.M. (2018). Distinguishing the differences in β-glucosylceramidase folds, dynamics, and actions informs therapeutic uses. J. Lipid Res. 59, 2262–2276.10.1194/jlr.R086629Search in Google Scholar PubMed PubMed Central
Boot, R.G., Verhoek, M., Donker-Koopman, W., Strijland, A., van Marle, J., Overkleeft, H.S., Wennekes, T., and Aerts, J.M. (2007). Identification of the non-lysosomal glucosylceramidase as β-glucosidase 2. J. Biol. Chem. 282, 1305–1312.10.1074/jbc.M610544200Search in Google Scholar PubMed
Charoenwattanasatien, R., Pengthaisong, S., Breen, I., Mutoh, R., Sansenya, S., Hua, Y., Tankrathok, A., Wu, L., Songsiriritthigul, C., Tanaka, H., Williams, S.J., et al. (2016). Bacterial β-glucosidase reveals the structural and functional basis of genetic defects in human glucocerebrosidase 2 (GBA2). ACS Chem. Biol. 11, 1891–1900.10.1021/acschembio.6b00192Search in Google Scholar PubMed PubMed Central
Davidson, B.A., Hassan, S., Garcia, E.J., Tayebi, N., and Sidransky, E. (2018). Exploring genetic modifiers of Gaucher disease: the next horizon. Hum. Mutat. 39, 1739–1751.10.1002/humu.23611Search in Google Scholar PubMed PubMed Central
Fuller, M., Rozaklis, T., Lovejoy, M., Zarrinkalam, K., Hopwood, J.J., and Meikle, P.J. (2008). Glucosylceramide accumulation is not confined to the lysosome in fibroblasts from patients with Gaucher disease. Mol. Genet. Metab. 93, 437–443.10.1016/j.ymgme.2007.11.011Search in Google Scholar PubMed
Hamler, R., Brignol, N., Clark, S.W., Morrison, S., Dungan, L.B., Chang, H.H., Khanna, R., Frascella, M., Valenzano, K.J., Benjamin, E.R., et al. (2017). Glucosylceramide and glucosylsphingosine quantitation by liquid chromatography-tandem mass spectrometry to enable in vivo preclinical studies of neuronopathic Gaucher disease. Anal. Chem. 89, 8288–8295.10.1021/acs.analchem.7b01442Search in Google Scholar PubMed
Hammer, M.B., Eleuch-Fayache, G., Schottlaender, L.V., Nehdi, H., Gibbs, J.R., Arepalli, S.K., Chong, S.B., Hernandez, D.G., Sailer, A., Liu, G., et al. (2013). Mutations in GBA2 cause differences in beta-glycosylceramidase folds, dynamics, and actions informs therapeutic uses. autosomal-recessive cerebellar ataxia with spasticity. Am. J. Hum. Genet. 92, 245–251.10.1016/j.ajhg.2012.12.012Search in Google Scholar PubMed PubMed Central
Harzer, K., and Yildiz, Y. (2015). High β-glucosidase (GBA) activity not attributable to GBA1 and GBA2 in live normal and enzyme-deficient fibroblasts may emphasise the role of additional GBAs. Biol. Chem. 396, 1241–1246.10.1515/hsz-2015-0144Search in Google Scholar PubMed
Harzer, K., Blech-Hermoni, Y., Goldin, E., Felderhoff-Mueser, U., Igney, C., Sidransky, E., and Yildiz, Y. (2012). Beta-glucosidase 1 (GBA1) is a second bile acid β-glucosidase in addition to β-glucosidase 2 (GBA2). Study in β-glucosidase deficient mice and humans. Biochem. Biophys. Res. Commun. 423, 308–312.10.1016/j.bbrc.2012.05.117Search in Google Scholar PubMed PubMed Central
Körschen, H.G., Yildiz, Y., Raju, D.N., Schonauer, S., Bönigk, W., Jansen, V., Kremmer, E., Kaupp, U.B., and Wachten, D. (2013). The non-lysosomal beta-glucosidase GBA2 is a non-integral membrane-associated protein at the endoplasmic reticulum (ER) and Golgi. J. Biol. Chem. 288, 3381–3393.10.1074/jbc.M112.414714Search in Google Scholar PubMed PubMed Central
Marques, A.R., Aten, J., Ottenhoff, R., van Roomen, C.P., Herrera Moro, D., Claessen, N., Vinueza Veloz, M.F., Zhou, K., Lin, Z., Mirzaian, M., et al. (2015). Reducing GBA2 activity ameliorates neuropathology in Niemann-Pick type C mice. PLoS One. 10. doi: 10.1371/journal.pone.0135889. eCollection 2015.10.1371/journal.pone.0135889Search in Google Scholar PubMed PubMed Central
Marschall, H.-U., Egestad, B., Matern, H., Matern, S., and Sjövall, J. (1987). Evidence for bile acid glucosides as normal constituents in human urine. FEBS Lett. 213, 411–417.10.1016/0014-5793(87)81532-6Search in Google Scholar PubMed
Martin, E., Schüle, R., Smets, K., Rastetter, A., Boukhris, A., Loureiro, J.L., Gonzalez, M.A., Mundwiller, E., Deconinck, T., Wessner, M., et al. (2013). Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia. Am. J. Hum. Genet. 92, 238–244.10.1016/j.ajhg.2012.11.021Search in Google Scholar PubMed PubMed Central
Matern, H., Gartzen, R., and Matern, S. (1992). Beta-glucosidase activity towards a bile acid glucoside in human liver. FEBS Lett. 314, 183–186.10.1016/0014-5793(92)80970-RSearch in Google Scholar PubMed
Matern, H., Heinemann, H., Legler, G., and Matern, S. (1997). Purification and characterization of a microsomal bile acid beta-glucosidase from human liver. J. Biol. Chem. 272, 11261–11267.10.1074/jbc.272.17.11261Search in Google Scholar PubMed
Orvisky, E., Sidransky, E., McKinney, C.E., Lamarca, M.E., Samimi, R., Krasnewich, D., Martin, B.M., and Ginns, E.I. (2000). Glucosylsphingosine accumulation in mice and patients with type 2 Gaucher disease begins early in gestation. Pediatr. Res. 48, 233–237.10.1203/00006450-200008000-00018Search in Google Scholar PubMed
Overkleeft, H.S., Renkema, G.H., Neele, J., Vianello, P., Hung, I.O., Strijland, A., van der Burg, A.M., Koomen, G.J., Pandit, U.K., and Aerts, J.M. (1998). Generation of specific deoxynojirimycin-type inhibitors of the non-lysosomal glucosylceramidase. J. Biol. Chem. 273, 26522–265227.10.1074/jbc.273.41.26522Search in Google Scholar PubMed
Ridley, C.M., Thur, K.E., Shanahan, J., Thillaiappan, N.B., Shen, A., Uhl, K., Walden, C.M., Rahim, A.A., Waddington, S.N., Platt, F.M., et al. (2013). β-Glucosidase 2 (GBA2) activity and imino sugar pharmacology. J. Biol. Chem. 288, 26052–26066.10.1074/jbc.M113.463562Search in Google Scholar PubMed PubMed Central
Schonauer, S., Körschen, H.G., Penno, A., Rennhack, A., Breiden, B., Sandhoff, K., Gutbrod, K., Dörmann, P., Raju, D.N., Haberkant, P., et al. (2017). Identification of a feedback loop involving β-glucosidase 2 and its product sphingosine sheds light on the molecular mechanisms in Gaucher disease. J. Biol. Chem. 292, 6177–6189.10.1074/jbc.M116.762831Search in Google Scholar PubMed PubMed Central
Sultana, S., Reichbauer, J., Schüle, R., Mochel, F., Synofzik, M., and van der Spoel, A.C. (2015). Lack of enzyme activity in GBA2 mutants associated with hereditary spastic paraplegia/cerebellar ataxia (SPG46). Biochem. Biophys. Res. Commun. 465, 35–40.10.1016/j.bbrc.2015.07.112Search in Google Scholar PubMed
Sultana, S., Truong, N.Y., Vieira, D.B., Wigger, J.G., Forrester, A.M., Veinotte, C.J., Berman, J.N., and van der Spoel, A.C. (2016). Characterization of the zebrafish homolog of β-glucosidase 2: A target of the drug miglustat. Zebrafish 13, 177–187.10.1089/zeb.2015.1152Search in Google Scholar PubMed
Tamargo, R.J., Velayati, A., Goldin, E., and Sidransky, E. (2012). The role of saposin C in Gaucher disease. Mol. Genet. Metab. 106, 257–263.10.1016/j.ymgme.2012.04.024Search in Google Scholar PubMed PubMed Central
van Weely, S., Brandsma, M., Strijland, A., Tager, J.M., and Aerts, J.M. (1993). Demonstration of the existence of a second, non-lysosomal glucocerebrosidase that is not deficient in Gaucher disease. Biochim. Biophys. Acta 1181, 55–62.10.1016/0925-4439(93)90090-NSearch in Google Scholar PubMed
Wennekes, T., Meijer, A.J., Groen, A.K., Boot, R.G., Groener, J.E., van Eijk, M., Ottenhoff, R., Bijl, N., Ghauharali, K., Song, H., et al. (2010). Dual-action lipophilic iminosugar improves glycemic control in obese rodents by reduction of visceral glycosphingolipids and buffering of carbohydrate assimilation. J. Med. Chem. 28, 689–698.10.1021/jm901281mSearch in Google Scholar PubMed
Yildiz, Y., Matern, H., Thompson, B., Allegood, J.C., Warren, R.L., Ramirez, D.M., Hammer, R.E., Hamra, F.K., Matern, S., and Russell, D.W. (2006). Mutation of β-glucosidase 2 causes glycolipid storage disease and impaired male fertility. J. Clin. Invest. 116, 2985–2994.10.1172/JCI29224Search in Google Scholar PubMed PubMed Central
Yildiz, Y., Hoffmann, P., Vom Dahl, S., Breiden, B., Sandhoff, R., Niederau, C., Horwitz, M., Karlsson, S., Filocamo, M., Elstein, D., et al. (2013). Functional and genetic characterization of the non-lysosomal glucosylceramidase 2 as a modifier for Gaucher disease. Orphanet J. Rare. Dis. 8, 151.10.1186/1750-1172-8-151Search in Google Scholar PubMed PubMed Central
Supplementary Material
The online version of this article offers supplementary material (https://doi.org/10.1515/hsz-2018-0438).
©2019 Walter de Gruyter GmbH, Berlin/Boston
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Articles in the same Issue
- Frontmatter
- Reviews
- Unforgettable force – crosstalk and memory of mechanosensitive structures
- Differential expression of DLG1 as a common trait in different human diseases: an encouraging issue in molecular pathology
- The effects of oxidative stress on the development of atherosclerosis
- Research Articles/Short Communications
- Protein Structure and Function
- Kinetically selective and potent inhibitors of HDAC8
- Assay of β-glucosidase 2 (GBA2) activity using lithocholic acid β-3-O-glucoside substrate for cultured fibroblasts and glucosylceramide for brain tissue
- Cell Biology and Signaling
- Changqin NO. 1 inhibits neuronal apoptosis via suppressing GAS5 expression in a traumatic brain injury mice model
- Nm23-H1 inhibits hypoxia induced epithelial-mesenchymal transition and stemness in non-small cell lung cancer cells
- Nodal promotes the malignancy of non-small cell lung cancer (NSCLC) cells via activation of NF-κB/IL-6 signals
- MCT1, MCT4 and CD147 expression and 3-bromopyruvate toxicity in colorectal cancer cells are modulated by the extracellular conditions
- Proteolysis
- Metalloprotease inhibitor profiles of human ADAM8 in vitro and in cell-based assays