Journal of Inherited Metabolic Disease

, Volume 35, Issue 6, pp 1081–1091 | Cite as

Cell surface associated glycohydrolases in normal and Gaucher disease fibroblasts

  • Massimo Aureli
  • Rosaria Bassi
  • Nicoletta Loberto
  • Stefano Regis
  • Alessandro Prinetti
  • Vanna Chigorno
  • Johannes M. Aerts
  • Rolf G. Boot
  • Mirella Filocamo
  • Sandro Sonnino
Original Article

Abstract

Gaucher disease (GD) is the most common lysosomal disorder and is caused by an inherited autosomal recessive deficiency in β-glucocerebrosidase. This enzyme, like other glycohydrolases involved in glycosphingolipid (GSL) metabolism, is present in both plasma membrane (PM) and intracellular fractions. We analyzed the activities of CBE-sensitive β-glucosidase (GBA1) and AMP-DNM-sensitive β-glucosidase (GBA2) in total cell lysates and PM of human fibroblast cell lines from control (normal) subjects and from patients with GD clinical types 1, 2, and 3. GBA1 activities in both total lysate and PM of GD fibroblasts were low, and their relative percentages were similar to those of control cells. In contrast, GBA2 activities were higher in GD cells than in control cells, and the degree of increase differed among the three GD types. The increase of GBA2 enzyme activity was correlated with increased expression of GBA2 protein as evaluated by QRT-PCR. Activities of β-galactosidase and β-hexosaminidase in PM were significantly higher for GD cells than for control cells and also showed significant differences among the three GD types, suggesting the occurrence of cross-talk among the enzymes involved in GSL metabolism. Our findings indicate that the profiles of glycohydrolase activities in PM may provide a valuable tool to refine the classification of GD into distinct clinical types.

References

  1. Aureli M, Masilamani AP, Illuzzi G et al (2009) Activity of plasma membrane beta-galactosidase and beta-glucosidase. FEBS Lett 583:2469–2473PubMedCrossRefGoogle Scholar
  2. Aureli M, Loberto N, Chigorno V, Prinetti A, Sonnino S (2011a) Remodeling of sphingolipids by plasma membrane associated enzymes. Neurochem Res 36:1636–1644PubMedCrossRefGoogle Scholar
  3. Aureli M, Loberto N, Lanteri P, Chigorno V, Prinetti A, Sonnino S (2011b) Cell surface sphingolipid glycohydrolases in neuronal differentiation and aging in culture. J Neurochem 116:891–899PubMedCrossRefGoogle Scholar
  4. Balwani M, Grace ME, Desnick RJ (2011) Gaucher disease: when molecular testing and clinical presentation disagree -the novel c.1226A>G(p.N370S)–RecNcil allele. J Inherit Metab Dis 34:789–793PubMedCrossRefGoogle Scholar
  5. Beutler E, Grabowski GA (2001) Gaucher disease. In: Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 3635–3668Google Scholar
  6. Boot RG, Verhoek M, Donker-Koopman W et al (2007) Identification of the non-lysosomal glucosylceramidase as beta-glucosidase 2. J Biol Chem 282:1305–1312PubMedCrossRefGoogle Scholar
  7. Crespo PM, Demichelis VT, Daniotti JL (2010) Neobiosynthesis of glycosphingolipids by plasma membrane-associated glycosyltransferases. J Biol Chem 285:29179–29190PubMedCrossRefGoogle Scholar
  8. de Fost M, Aerts JM, Hollak CE (2003) Gaucher disease: from fundamental research to effective therapeutic interventions. Neth J Med 61:3–8PubMedGoogle Scholar
  9. Dekker N, Voorn-Brouwer T, Verhoek M et al (2011) The cytosolic beta-glucosidase GBA3 does not influence type 1 Gaucher disease manifestation. Blood Cells Mol Dis 46:19–26PubMedCrossRefGoogle Scholar
  10. Filocamo M, Mazzotti R, Stroppiano M et al (2002) Analysis of the glucocerebrosidase gene and mutation profile in 144 Italian gaucher patients. Hum Mutat 20:234–235PubMedCrossRefGoogle Scholar
  11. Filocamo M, Mazzotti R, Stroppiano M et al (2004) Early visual seizures and progressive myoclonus epilepsy in neuronopathic Gaucher disease due to a rare compound heterozygosity (N188S/S107L). Epilepsia 45:1154–1157Google Scholar
  12. Filocamo M, Grossi S, Stroppiano M et al (2005) Homozygosity for a non-pseudogene complex glucocerebrosidase allele as cause of an atypical neuronopathic form of Gaucher disease. Am J Med Genet A 134A:95–96PubMedCrossRefGoogle Scholar
  13. Fuller M, Lovejoy M, Hopwood JJ, Meikle PJ (2005) Immunoquantification of beta-glucosidase: diagnosis and prediction of severity in Gaucher disease. Clin Chem 51:2200–2202PubMedCrossRefGoogle Scholar
  14. Fuller M, Rozaklis T, Lovejoy M, Zarrinkalam K, Hopwood JJ, Meikle PJ (2008) Glucosylceramide accumulation is not confined to the lysosome in fibroblasts from patients with Gaucher disease. Mol Genet Metab 93:437–443PubMedCrossRefGoogle Scholar
  15. Ghauharali-van der Vlugt K, Langeveld M, Poppema A et al (2008) Prominent increase in plasma ganglioside GM3 is associated with clinical manifestations of type I Gaucher disease. Clin Chim Acta 389:109–113PubMedCrossRefGoogle Scholar
  16. Goker-Alpan O, Hruska KS, Orvisky E et al (2005) Divergent phenotypes in Gaucher disease implicate the role of modifiers. J Med Genet 42:e37PubMedCrossRefGoogle Scholar
  17. Hruska KS, LaMarca ME, Scott CR, Sidransky E (2008) Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA). Hum Mutat 29:567–583PubMedCrossRefGoogle Scholar
  18. Huitema K, van den Dikkenberg J, Brouwers JF, Holthuis JC (2004) Identification of a family of animal sphingomyelin synthases. EMBO J 23:33–44PubMedCrossRefGoogle Scholar
  19. Kacher Y, Futerman AH (2006) Genetic diseases of sphingolipid metabolism: pathological mechanisms and therapeutic options. FEBS Lett 580:5510–5517PubMedCrossRefGoogle Scholar
  20. Kawamura S, Sato I, Wada T et al (2011) Plasma membrane-associated sialidase (NEU3) regulates progression of prostate cancer to androgen-independent growth through modulation of androgen receptor signaling. Cell Death Differ 19:170–179PubMedCrossRefGoogle Scholar
  21. Kolter T, Sandhoff K (2005) Principles of lysosomal membrane digestion: stimulation of sphingolipid degradation by sphingolipid activator proteins and anionic lysosomal lipids. Annu Rev Cell Dev Biol 21:81–103PubMedCrossRefGoogle Scholar
  22. Lachmann RH, Grant IR, Halsall D, Cox TM (2004) Twin pairs showing discordance of phenotype in adult Gaucher's disease. QJM 97:199–204PubMedCrossRefGoogle Scholar
  23. Ledesma MD, Prinetti A, Sonnino S, Schuchman EH (2011) Brain pathology in Niemann Pick disease type A: insights from the acid sphingomyelinase knockout mice. J Neurochem 116:779–788PubMedCrossRefGoogle Scholar
  24. Levade T, Jaffrezou JP (1999) Signalling sphingomyelinases: which, where, how and why? Biochim Biophys Acta 1438:1–17PubMedCrossRefGoogle Scholar
  25. Maccioni HJ (2007) Glycosylation of glycolipids in the Golgi complex. J Neurochem 103(Suppl 1):81–90PubMedCrossRefGoogle Scholar
  26. Mencarelli S, Cavalieri C, Magini A et al (2005) Identification of plasma membrane associated mature beta-hexosaminidase A, active towards GM2 ganglioside, in human fibroblasts. FEBS Lett 579:5501–5506PubMedCrossRefGoogle Scholar
  27. Monti E, Bassi MT, Papini N et al (2000) Identification and expression of NEU3, a novel human sialidase associated to the plasma membrane. Biochem J 349:343–351PubMedCrossRefGoogle Scholar
  28. Overkleeft HS, Renkema GH, Neele J et al (1998) Generation of specific deoxynojirimycin-type inhibitors of the non-lysosomal glucosylceramidase. J Biol Chem 273:26522–26527PubMedCrossRefGoogle Scholar
  29. Papini N, Anastasia L, Tringali C et al (2004) The plasma membrane-associated sialidase MmNEU3 modifies the ganglioside pattern of adjacent cells supporting its involvement in cell-to-cell interactions. J Biol Chem 279:16989–16995PubMedCrossRefGoogle Scholar
  30. Pastores GM, Hughes DA (2010) Gaucher disease. In: Pagon RA, Bird TD, Dolan CR, Stephens K (eds) GeneReviews. University of Washington, SeattleGoogle Scholar
  31. Preti A, Fiorilli A, Lombardo A, Caimi L, Tettamanti G (1980) Occurrence of sialyltransferase activity in the synaptosomal membranes prepared from calf brain cortex. J Neurochem 35:281–296PubMedCrossRefGoogle Scholar
  32. Reczek D, Schwake M, Schroder J et al (2007) LIMP-2 is a receptor for lysosomal mannose-6-phosphate-independent targeting of beta-glucocerebrosidase. Cell 131:770–783PubMedCrossRefGoogle Scholar
  33. Reddy A, Caler EV, Andrews NW (2001) Plasma membrane repair is mediated by Ca(2+)-regulated exocytosis of lysosomes. Cell 106:157–169PubMedCrossRefGoogle Scholar
  34. Regis S, Grossi S, Lualdi S, Biancheri R, Filocamo M (2005) Diagnosis of Pelizaeus-Merzbacher disease: detection of proteolipid protein gene copy number by real-time PCR. Neurogenetics 6:73–78PubMedCrossRefGoogle Scholar
  35. Romano M, Danek G, Baralle F et al (2000) Functional characterisation of the novel mutation IVS 8 (-11delC)(-14T->A) in the intron 8 of the glucocerebrosidase gene of two Italian siblings with Gaucher disease type I. Blood Cells Mol Dis 26:171–176Google Scholar
  36. Sardiello M, Palmieri M, di Ronza A et al (2009) A gene network regulating lysosomal biogenesis and function. Science 325:473–477PubMedGoogle Scholar
  37. Scandroglio F, Venkata JK, Loberto N et al (2008) Lipid content of brain, brain membrane lipid domains, and neurons from acid sphingomyelinase deficient mice. J Neurochem 107:329–338PubMedCrossRefGoogle Scholar
  38. Sibille A, Eng CM, Kim SJ, Pastores G, Grabowski GA (1993) Phenotype/genotype correlations in Gaucher disease type I: clinical and therapeutic implications. Am J Hum Genet 52:1094–1101PubMedGoogle Scholar
  39. Sillence DJ, Puri V, Marks DL et al (2002) Glucosylceramide modulates membrane traffic along the endocytic pathway. J Lipid Res 43:1837–1845PubMedCrossRefGoogle Scholar
  40. Slife CW, Wang E, Hunter R et al (1989) Free sphingosine formation from endogenous substrates by a liver plasma membrane system with a divalent cation dependence and a neutral pH optimum. J Biol Chem 264:10371–10377PubMedGoogle Scholar
  41. Sonnino S, Prinetti A, Mauri L, Chigorno V, Tettamanti G (2006) Dynamic and structural properties of sphingolipids as driving forces for the formation of membrane domains. Chem Rev 106:2111–2125PubMedCrossRefGoogle Scholar
  42. Sonnino S, Mauri L, Chigorno V, Prinetti A (2007) Gangliosides as components of lipid membrane domains. Glycobiology 17:1R–13RPubMedCrossRefGoogle Scholar
  43. Sonnino S, Aureli M, Loberto N, Chigorno V, Prinetti A (2010) Fine tuning of cell functions through remodeling of glycosphingolipids by plasma membrane-associated glycohydrolases. FEBS Lett 584:1914–1922PubMedCrossRefGoogle Scholar
  44. Stenson PD, Mort M, Ball EV et al (2009) The human gene mutation database: 2008 update. Genome Med 1:13PubMedCrossRefGoogle Scholar
  45. Tani M, Ito M, Igarashi Y (2007) Ceramide/sphingosine/sphingosine 1-phosphate metabolism on the cell surface and in the extracellular space. Cell Signal 19:229–237PubMedCrossRefGoogle Scholar
  46. Theophilus B, Latham T, Grabowski GA, Smith FI (1989) Gaucher disease: molecular heterogeneity and phenotype-genotype correlations. Am J Hum Genet 45:212–225PubMedGoogle Scholar
  47. Valaperta R, Chigorno V, Basso L et al (2006) Plasma membrane production of ceramide from ganglioside GM3 in human fibroblasts. FASEB J 20:1227–1229PubMedCrossRefGoogle Scholar
  48. Valaperta R, Valsecchi M, Rocchetta F et al (2007) Induction of axonal differentiation by silencing plasma membrane-associated sialidase Neu3 in neuroblastoma cells. J Neurochem 100:708–719PubMedCrossRefGoogle Scholar
  49. van Weely S, Brandsma M, Strijland A, Tager JM, Aerts JM (1993) Demonstration of the existence of a second, non-lysosomal glucocerebrosidase that is not deficient in Gaucher disease. Biochim Biophys Acta 1181:55–62PubMedCrossRefGoogle Scholar
  50. Vitner EB, Platt FM, Futerman AH (2010) Common and uncommon pathogenic cascades in lysosomal storage diseases. J Biol Chem 285:20423–20427PubMedCrossRefGoogle Scholar
  51. Wennekes T, van den Berg RJ, Boot RG, van der Marel GA, Overkleeft HS, Aerts JM (2009) Glycosphingolipids–nature, function, and pharmacological modulation. Angew Chem Int Ed Engl 48:8848–8869PubMedCrossRefGoogle Scholar
  52. Yonezawa N, Amari S, Takahashi K et al (2005) Participation of the nonreducing terminal beta-galactosyl residues of the neutral N-linked carbohydrate chains of porcine zona pellucida glycoproteins in sperm-egg binding. Mol Reprod Dev 70:222–227PubMedCrossRefGoogle Scholar

Copyright information

© SSIEM and Springer 2012

Authors and Affiliations

  • Massimo Aureli
    • 1
  • Rosaria Bassi
    • 1
  • Nicoletta Loberto
    • 1
  • Stefano Regis
    • 2
  • Alessandro Prinetti
    • 1
  • Vanna Chigorno
    • 1
  • Johannes M. Aerts
    • 3
  • Rolf G. Boot
    • 3
  • Mirella Filocamo
    • 2
  • Sandro Sonnino
    • 1
    • 4
  1. 1.Department of Medical Chemistry, Biochemistry and BiotechnologyUniversity of MilanSegrateItaly
  2. 2.“Diagnosi Pre-Postnatale Malattie Metaboliche” LaboratoryG. Gaslini InstituteGenovaItaly
  3. 3.Department of Medical Biochemistry, Academic Medical CenterUniversity of AmsterdamAmsterdamthe Netherlands
  4. 4.Dipartimento di Chimica, Biochimica e Biotecnologie per la MedicinaUniversità degli Studi di MilanoSegrateItaly

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