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Current and Novel Aspects on the Non-lysosomal β-Glucosylceramidase GBA2

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An Erratum to this article was published on 28 January 2016

Abstract

The non-lysosomal β-glucosylceramidase GBA2 (EC3.2.1.45, GH116) is ubiquitously expressed in various mammal tissues and cell types where it catalyzes the hydrolysis of glucosylceramide into glucose and ceramide. Although it has been known for many years that the central nervous system is the main site of GBA2 expression and activity, little information has been available so far on the role of this protein in the neuronal development, senescence and homeostasis. In the present review, we summarize the state-of-the art of this enzyme and in particular, we focus on the current knowledge on its structure, its physico-chemical properties and its subcellular localization. Data on the involvement of GBA2 in physiopathological processes are also described, with particular emphasis on the studies that have indicated the direct involvement of GBA2 in neuronal development and neurological disorders. A discussion of some open questions and future perspectives related to GBA2 are finally reported. We conclude that further investigations on this β-glucosylceramidase will provide new clues about the physiology of the central nervous system.

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References

  1. Sonnino S, Prinetti A, Mauri L et al (2006) Dynamic and structural properties of sphingolipids as driving forces for the formation of membrane domains. Chem Rev 106:2111–2125. doi:10.1021/cr0100446

    Article  CAS  PubMed  Google Scholar 

  2. Folch-Pi J (1968) The composition of nervous membranes. Prog Brain Res 29:1–17. doi:10.1016/S0079-6123(08)64146-1

    Article  CAS  PubMed  Google Scholar 

  3. Aureli M, Loberto N, Chigorno V et al (2011) Remodeling of sphingolipids by plasma membrane associated enzymes. Neurochem Res 36:1636–1644. doi:10.1007/s11064-010-0360-7

    Article  CAS  PubMed  Google Scholar 

  4. Matern H, Gartzen R, Matern S (1992) Beta-glucosidase activity towards a bile acid glucoside in human liver. FEBS Lett 314:183–186. doi:10.1016/0014-5793(92)80970-R

    Article  CAS  PubMed  Google Scholar 

  5. van Weely S, Brandsma M, Strijland A et al (1993) Demonstration of the existence of a second, non-lysosomal glucocerebrosidase that is not deficient in Gaucher disease. Biochim Biophys Acta 1181:55–62

    Article  PubMed  Google Scholar 

  6. Matern H, Heinemann H, Legler G et al (1997) Purification and characterization of a microsomal bile acid beta-glucosidase from human liver. J Biol Chem 272:11261–11267

    Article  CAS  PubMed  Google Scholar 

  7. Matern H, Boermans H, Lottspeich F et al (2001) Molecular cloning and expression of human bile acid beta-glucosidase. J Biol Chem 276:37929–37933. doi:10.1074/jbc.M104290200

    CAS  PubMed  Google Scholar 

  8. Yildiz Y, Matern H, Thompson B et al (2006) Mutation of beta-glucosidase 2 causes glycolipid storage disease and impaired male fertility. J Clin Invest 116:2985–2994. doi:10.1172/JCI29224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Boot RG, Verhoek M, Donker-Koopman W et al (2007) Identification of the non-lysosomal glucosylceramidase as beta-glucosidase 2. J Biol Chem 282:1305–1312. doi:10.1074/jbc.M610544200

    Article  CAS  PubMed  Google Scholar 

  10. Korschen HG, Yildiz Y, Raju DN et al (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. doi:10.1074/jbc.M112.414714

    Article  PubMed  PubMed Central  Google Scholar 

  11. Cobucci-Ponzano B, Aurilia V, Riccio G et al (2010) A new archaeal beta-glycosidase from Sulfolobus solfataricus: seeding a novel retaining beta-glycan-specific glycoside hydrolase family along with the human non-lysosomal glucosylceramidase GBA2. J Biol Chem 285:20691–20703. doi:10.1074/jbc.M109.086470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zecca L, Mesonero JE, Stutz A et al (1998) Intestinal lactase-phlorizin hydrolase (LPH): the two catalytic sites; the role of the pancreas in pro-LPH maturation. FEBS Lett 435:225–228. doi:10.1016/S0014-5793(98)01076-X

    Article  CAS  PubMed  Google Scholar 

  13. Rempel BP, Withers SG (2008) Covalent inhibitors of glycosidases and their applications in biochemistry and biology. Glycobiology 18:570–586. doi:10.1093/glycob/cwn041

    Article  CAS  PubMed  Google Scholar 

  14. Koshland DE Jr, Clarke E (1953) Mechanism of hydrolysis of adenosinetriphosphate catalyzed by lobster muscle. J Biol Chem 205:917–924

    CAS  PubMed  Google Scholar 

  15. Kallemeijn WW, Witte MD, Voorn-Brouwer TM et al (2014) A sensitive gel-based method combining distinct cyclophellitol-based probes for the identification of acid/base residues in human retaining beta-glucosidases. J Biol Chem 289:35351–35362. doi:10.1074/jbc.M114.593376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Witte MD, Kallemeijn WW, Aten J et al (2010) Ultrasensitive in situ visualization of active glucocerebrosidase molecules. Nat Chem Biol 6:907–913. doi:10.1038/nchembio.466

    Article  CAS  PubMed  Google Scholar 

  17. Kallemeijn WW, Li KY, Witte MD et al (2012) Novel activity-based probes for broad-spectrum profiling of retaining beta-exoglucosidases in situ and in vivo. Angew Chem Int Ed Engl 51:12529–12533. doi:10.1002/anie.201207771

    Article  CAS  PubMed  Google Scholar 

  18. Ridley CM, Thur KE, Shanahan J et al (2013) beta-Glucosidase 2 (GBA2) activity and imino sugar pharmacology. J Biol Chem 288:26052–26066. doi:10.1074/jbc.M113.463562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Elbein AD (1991) Glycosidase inhibitors: inhibitors of N-linked oligosaccharide processing. FASEB J 5:3055–3063

    CAS  PubMed  Google Scholar 

  20. Platt FM, Neises GR, Dwek RA et al (1994) N-butyldeoxynojirimycin is a novel inhibitor of glycolipid biosynthesis. J Biol Chem 269:8362–8365

    CAS  PubMed  Google Scholar 

  21. Overkleeft HS, Renkema GH, Neele J et al (1998) Generation of specific deoxynojirimycin-type inhibitors of the non-lysosomal glucosylceramidase. J Biol Chem 273:26522–26527

    Article  CAS  PubMed  Google Scholar 

  22. Korkotian E, Schwarz A, Pelled D et al (1999) Elevation of intracellular glucosylceramide levels results in an increase in endoplasmic reticulum density and in functional calcium stores in cultured neurons. J Biol Chem 274:21673–21678

    Article  CAS  PubMed  Google Scholar 

  23. Aureli M, Samarani M, Loberto N et al (2014) The glycosphingolipid hydrolases in the central nervous system. Mol Neurobiol 50:76–87. doi:10.1007/s12035-013-8592-6

    Article  CAS  PubMed  Google Scholar 

  24. Aureli M, Loberto N, Bassi R et al (2011) Plasma membrane-associated glycohydrolases activation by extracellular acidification due to proton exchangers. Neurochem Res 37:1296–1307. doi:10.1007/s11064-012-0725-1

    Article  Google Scholar 

  25. van Meer G, Sillence D, Sprong H et al (1999) Transport of (glyco)sphingolipids in and between cellular membranes; multidrug transporters and lateral domains. Biosci Rep 19:327–333. doi:10.1023/A:1020506726480

    Article  PubMed  Google Scholar 

  26. Aureli M, Masilamani AP, Illuzzi G et al (2009) Activity of plasma membrane beta-galactosidase and beta-glucosidase. FEBS Lett 583:2469–2473. doi:10.1016/j.febslet.2009.06.048

    Article  CAS  PubMed  Google Scholar 

  27. Gonzalez-Carmona MA, Sandhoff R, Tacke F et al (2012) Beta-glucosidase 2 knockout mice with increased glucosylceramide show impaired liver regeneration. Liver Int 32:1354–1362. doi:10.1111/j.1478-3231.2012.02841.x

    Article  CAS  PubMed  Google Scholar 

  28. Raju D, Schonauer S, Hamzeh H et al (2015) Accumulation of glucosylceramide in the absence of the beta-glucosidase GBA2 alters cytoskeletal dynamics. PLoS Genet 11:e1005063. doi:10.1371/journal.pgen.1005063

    Article  PubMed  PubMed Central  Google Scholar 

  29. Walden CM, Sandhoff R, Chuang CC et al (2007) Accumulation of glucosylceramide in murine testis, caused by inhibition of beta-glucosidase 2: implications for spermatogenesis. J Biol Chem 282:32655–32664. doi:10.1074/jbc.M702387200

    Article  CAS  PubMed  Google Scholar 

  30. Amory JK, Muller CH, Page ST et al (2007) Miglustat has no apparent effect on spermatogenesis in normal men. Hum Reprod 22:702–707. doi:10.1093/humrep/del414

    Article  CAS  PubMed  Google Scholar 

  31. Sultana S, Reichbauer J, Schule R et al (2015) Lack of enzyme activity in GBA2 mutants associated with hereditary spastic paraplegia/cerebellar ataxia (SPG46). Biochem Biophys Res Commun 465:35–40. doi:10.1016/j.bbrc.2015.07.112

    Article  CAS  PubMed  Google Scholar 

  32. Hammer MB, Eleuch-Fayache G, Schottlaender LV et al (2013) Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity. Am J Hum Genet 92:245–251. doi:10.1016/j.ajhg.2012.12.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Martin E, Schule R, Smets K 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. doi:10.1016/j.ajhg.2012.11.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Citterio A, Arnoldi A, Panzeri E et al (2014) Mutations in CYP2U1, DDHD2 and GBA2 genes are rare causes of complicated forms of hereditary spastic paraparesis. J Neurol 261:373–381. doi:10.1007/s00415-013-7206-6

    Article  CAS  PubMed  Google Scholar 

  35. Votsi C, Zamba-Papanicolaou E, Middleton LT et al (2014) A novel GBA2 gene missense mutation in spastic ataxia. Ann Hum Genet 78:13–22. doi:10.1111/ahg.12045

    Article  CAS  PubMed  Google Scholar 

  36. Aureli M, Loberto N, Lanteri P et al (2011) Cell surface sphingolipid glycohydrolases in neuronal differentiation and aging in culture. J Neurochem 116:891–899. doi:10.1111/j.1471-4159.2010.07019.x

    Article  CAS  PubMed  Google Scholar 

  37. Schondorf DC, Aureli M, McAllister FE et al (2014) iPSC-derived neurons from GBA1-associated Parkinson’s disease patients show autophagic defects and impaired calcium homeostasis. Nat Commun 5:4028. doi:10.1038/ncomms5028

    Article  PubMed  Google Scholar 

  38. Sorli SC, Colie S, Albinet V et al (2013) The nonlysosomal beta-glucosidase GBA2 promotes endoplasmic reticulum stress and impairs tumorigenicity of human melanoma cells. FASEB J 27:489–498. doi:10.1096/fj.12-215152

    Article  CAS  PubMed  Google Scholar 

  39. Di Rosa M, Sanfilippo C, Libra M et al (2015) Different pediatric brain tumors are associated with different gene expression profiling. Acta Histochem 117:477–485. doi:10.1016/j.acthis.2015.02.010

    Article  PubMed  Google Scholar 

  40. Yildiz Y, Hoffmann P, Vom Dahl S 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. doi:10.1186/1750-1172-8-151

    Article  PubMed  PubMed Central  Google Scholar 

  41. Burke DG, Rahim AA, Waddington SN et al (2013) Increased glucocerebrosidase (GBA) 2 activity in GBA1 deficient mice brains and in Gaucher leucocytes. J Inherit Metab Dis 36:869–872. doi:10.1007/s10545-012-9561-3

    Article  CAS  PubMed  Google Scholar 

  42. Aureli M, Bassi R, Loberto N et al (2012) Cell surface associated glycohydrolases in normal and Gaucher disease fibroblasts. J Inherit Metab Dis 35:1081–1091. doi:10.1007/s10545-012-9478-x

    Article  CAS  PubMed  Google Scholar 

  43. Mistry PK, Liu J, Sun L et al (2014) Glucocerebrosidase 2 gene deletion rescues type 1 Gaucher disease. Proc Natl Acad Sci USA 111:4934–4939. doi:10.1073/pnas.1400768111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ashe KM, Bangari D, Li L et al (2011) Iminosugar-based inhibitors of glucosylceramide synthase increase brain glycosphingolipids and survival in a mouse model of Sandhoff disease. PLoS ONE 6:e21758. doi:10.1371/journal.pone.0021758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Nietupski JB, Pacheco JJ, Chuang WL et al (2012) Iminosugar-based inhibitors of glucosylceramide synthase prolong survival but paradoxically increase brain glucosylceramide levels in Niemann-Pick C mice. Mol Genet Metab 105:621–628. doi:10.1016/j.ymgme.2012.01.020

    Article  CAS  PubMed  Google Scholar 

  46. Scharl M, Leucht K, Frey-Wagner I et al (2011) Knock-out of beta-glucosidase 2 has no influence on dextran sulfate sodium-induced colitis. Digestion 84:156–167. doi:10.1159/000327380

    Article  CAS  PubMed  Google Scholar 

  47. Loberto N, Tebon M, Lampronti I et al (2014) GBA2-encoded beta-glucosidase activity is involved in the inflammatory response to Pseudomonas aeruginosa. PLoS ONE 9:e104763. doi:10.1371/journal.pone.0104763

    Article  PubMed  PubMed Central  Google Scholar 

  48. Hornbeck PV, Zhang B, Murray B et al (2015) PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucl Acids Res 43:D512–D520. doi:10.1093/nar/gku1267

    Article  PubMed  PubMed Central  Google Scholar 

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    Authors and Affiliations

    1. Department of Medical Biotechnology and Translational Medicine, University of Milano, Milano, Italy

      Aureli Massimo, Samarani Maura, Loberto Nicoletta, Mancini Giulia, Murdica Valentina, Chiricozzi Elena, Prinetti Alessandro, Bassi Rosaria & Sonnino Sandro

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    1. Aureli Massimo
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    Correspondence to Sonnino Sandro.

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    Special Issue: 40th Year of Neurochemical Research.

    Aureli Massimo and Samarani Maura have contributed equally to the work.

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    Massimo, A., Maura, S., Nicoletta, L. et al. Current and Novel Aspects on the Non-lysosomal β-Glucosylceramidase GBA2. Neurochem Res 41, 210–220 (2016). https://doi.org/10.1007/s11064-015-1763-2

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