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Link to original content: http://dx.doi.org/10.1007/s00401-010-0741-7
Glucocerebrosidase is present in α-synuclein inclusions in Lewy body disorders | Acta Neuropathologica Skip to main content

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Glucocerebrosidase is present in α-synuclein inclusions in Lewy body disorders

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Abstract

Mutations in the gene encoding the lysosomal enzyme glucocerebrosidase, known to cause Gaucher disease (GD), are a risk factor for the development of Parkinson disease (PD) and related disorders. This association is based on the concurrence of parkinsonism and GD, the identification of glucocerebrosidase mutations in cohorts with PD from centers around the world, and neuropathologic findings. The contribution of glucocerebrosidase to the development of parkinsonian pathology was explored by studying seven brain samples from subjects carrying glucocerebrosidase mutations with pathologic diagnoses of PD and/or Lewy body dementia. Three individuals had GD and four were heterozygous for glucocerebrosidase mutations. All cases had no known family history of PD and the mean age of disease onset was 59 years (range 42–77). Immunofluorescence studies on brain tissue samples from patients with parkinsonism associated with glucocerebrosidase mutations showed that glucocerebrosidase was present in 32–90% of Lewy bodies (mean 75%), some ubiquitinated and others non-ubiquitinated. In samples from seven subjects without mutations, <10% of Lewy bodies were glucocerebrosidase positive (mean 4%). This data demonstrates that glucocerebrosidase can be an important component of α-synuclein-positive pathological inclusions. Unraveling the role of mutant glucocerebrosidase in the development of this pathology will further our understanding of the lysosomal pathways that likely contribute to the formation and/or clearance of these protein aggregates.

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References

  1. Aharon-Peretz J, Rosenbaum H, Gershoni-Baruch R (2004) Mutations in the glucocerebrosidase gene and Parkinson’s disease in Ashkenazi Jews. N Engl J Med 351:1972–1977

    Article  CAS  PubMed  Google Scholar 

  2. Baba M, Nakajo S, Tu PH et al (1998) Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies. Am J Pathol 152:879–884

    CAS  PubMed  Google Scholar 

  3. Braak H, Del Tredici K, Rub U et al (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211

    Article  PubMed  Google Scholar 

  4. Bras J, Paisan-Ruiz C, Guerreiro R et al (2009) Complete screening for glucocerebrosidase mutations in Parkinson disease patients from Portugal. Neurobiol Aging 30:1515–1517

    Article  CAS  PubMed  Google Scholar 

  5. Clark LN, Kartsaklis LA, Wolf Gilbert R et al (2009) Association of glucocerebrosidase mutations with dementia with Lewy bodies. Arch Neurol 66:578–583

    Article  PubMed  Google Scholar 

  6. Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D (2004) Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305:1292–1295

    Article  CAS  PubMed  Google Scholar 

  7. Duda JE, Giasson BI, Gur TL et al (2000) Immunohistochemical and biochemical studies demonstrate a distinct profile of α-synuclein permutations in multiple system atrophy. J Neuropathol Exp Neurol 59:830–841

    CAS  PubMed  Google Scholar 

  8. Gai WP, Yuan HX, Li XQ et al (2000) In situ and in vitro study of colocalization and segregation of alpha-synuclein, ubiquitin, and lipids in Lewy bodies. Exp Neurol 166:324–333

    Article  CAS  PubMed  Google Scholar 

  9. Gan-Or Z, Giladi N, Rozovski U et al (2008) Genotype-phenotype correlations between GBA mutations and Parkinson disease risk and onset. Neurology 70:2277–2283

    Article  CAS  PubMed  Google Scholar 

  10. Goedert M (2001) Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci 2:492–501

    Article  CAS  PubMed  Google Scholar 

  11. Goker-Alpan O, Giasson BI, Eblan MJ et al (2006) Glucocerebrosidase mutations are an important risk factor for Lewy body disorders. Neurology 67:908–910

    Article  CAS  PubMed  Google Scholar 

  12. Goker-Alpan O, Lopez G, Vithayathil J et al (2008) The spectrum of parkinsonian manifestations associated with glucocerebrosidase mutations. Arch Neurol 65:1353–1357

    Article  PubMed  Google Scholar 

  13. Goker-Alpan O, Schiffmann R, LaMarca ME et al (2004) Parkinsonism among Gaucher disease carriers. J Med Genet 41:937–940

    Article  CAS  PubMed  Google Scholar 

  14. Hein LK, Duplock S, Hopwood JJ, Fuller M (2008) Lipid composition of microdomains is altered in a cell model of Gaucher disease. J Lipid Res 49:1725–1734

    Article  CAS  PubMed  Google Scholar 

  15. Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992) Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 55:181–184

    Article  CAS  PubMed  Google Scholar 

  16. Lwin A, Orvisky E, Goker-Alpan O, LaMarca ME, Sidransky E (2004) Glucocerebrosidase mutations in subjects with parkinsonism. Mol Genet Metab 81:70–73

    Article  CAS  PubMed  Google Scholar 

  17. McKeith IG, Dickson DW, Lowe J et al (2005) Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65:1863–1872

    Article  CAS  PubMed  Google Scholar 

  18. Mitsui J, Mizuta I, Toyoda A et al (2009) Mutations for Gaucher disease confer high susceptibility to Parkinson disease. Arch Neurol 66:571–576

    Article  PubMed  Google Scholar 

  19. Neumann J, Bras J, Deas E et al (2009) Glucocerebrosidase mutations in clinical and pathologically proven Parkinson’s disease. Brain 132:1783–1794

    Article  PubMed  Google Scholar 

  20. Nichols WC, Pankratz N, Marek DK et al (2009) Mutations in GBA are associated with familial Parkinson disease susceptibility and age at onset. Neurology 72:310–316

    Article  CAS  PubMed  Google Scholar 

  21. Norris EH, Giasson BI, Lee VM (2004) Alpha-synuclein: normal function and role in neurodegenerative diseases. Curr Top Dev Biol 60:17–54

    Article  CAS  PubMed  Google Scholar 

  22. Orvisky E, Park JK, LaMarca ME et al (2002) Glucosylsphingosine accumulation in tissues from patients with Gaucher disease: correlation with phenotype and genotype. Mol Genet Metab 76:262–270

    Article  CAS  PubMed  Google Scholar 

  23. Polymeropoulos MH, Lavedan C, Leroy E et al (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047

    Article  CAS  PubMed  Google Scholar 

  24. Ramakrishnan M, Jensen PH, Marsh D (2006) Association of alpha-synuclein and mutants with lipid membranes: spin-label ESR and polarized IR. Biochemistry 45:3386–3395

    Article  CAS  PubMed  Google Scholar 

  25. Romijn HJ, van Uum JF, Breedijk I et al (1999) Double immunolabeling of neuropeptides in the human hypothalamus as analyzed by confocal laser scanning fluorescence microscopy. J Histochem Cytochem 47:229–236

    CAS  PubMed  Google Scholar 

  26. Sato C, Morgan A, Lang AE et al (2005) Analysis of the glucocerebrosidase gene in Parkinson’s disease. Mov Disord 20:367–370

    Article  PubMed  Google Scholar 

  27. Shults CW (2006) Lewy bodies. Proc Natl Acad Sci USA 103:1661–1668

    Article  CAS  PubMed  Google Scholar 

  28. Sidransky E, Nalls MA, Aasly JO et al (2009) Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med 361:1651–1661

    Article  CAS  PubMed  Google Scholar 

  29. Spillantini MG, Schmidt ML, Lee VM et al (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840

    Article  CAS  PubMed  Google Scholar 

  30. Tayebi N, Reissner KJ, Lau EK et al (1998) Genotypic heterogeneity and phenotypic variation among patients with type 2 Gaucher’s disease. Pediatr Res 43:571–578

    Article  CAS  PubMed  Google Scholar 

  31. Tayebi N, Walker J, Stubblefield B et al (2003) Gaucher disease with parkinsonian manifestations: does glucocerebrosidase deficiency contribute to a vulnerability to parkinsonism? Mol Genet Metab 79:104–109

    Article  CAS  PubMed  Google Scholar 

  32. Wong K, Sidransky E, Verma A et al (2004) Neuropathology provides clues to the pathophysiology of Gaucher disease. Mol Genet Metab 82:192–207

    Article  CAS  PubMed  Google Scholar 

  33. Ziegler SG, Eblan MJ, Gutti U et al (2007) Glucocerebrosidase mutations in Chinese subjects from Taiwan with sporadic Parkinson disease. Mol Genet Metab 91:195–200

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Stephen Wincovitch for technical assistance with confocal microscopy, and Julia Fekecs and Jae Choi for preparation of the figures. This work was supported by the Intramural Research Program of the National Human Genome Research Institute and Udall Centre of Excellence in Parkinson’s Disease Research Grant (NS053488).

Conflict of interest

The authors of this manuscript have no conflicts of interest to disclose.

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Authors and Affiliations

  1. Section on Molecular Neurogenetics, Medical Genetics Branch, NHGRI, National Institutes of Health, Building 35, Room 1A213, 35 Convent Drive, MSC 3708, Bethesda, MD, 20892-3708, USA

    Ozlem Goker-Alpan, Barbara K. Stubblefield & Ellen Sidransky

  2. Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA

    Benoit I. Giasson

Authors
  1. Ozlem Goker-Alpan
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  2. Barbara K. Stubblefield
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  3. Benoit I. Giasson
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  4. Ellen Sidransky
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Corresponding author

Correspondence to Ellen Sidransky.

Additional information

In memoriam: With love and gratitude, we remember Mary E. LaMarca, who contributed to this work by sharing her ideas, offering constructive criticism and assisting in the preparation of the figures.

Electronic supplementary material

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Reactivity against glucocerebrosidase in LBs and intraneuronal inclusions after Sudan Black staining, using different anti-GC antibodies:

Figure S1

Representative sections from cases 1 and 4 (also shown in Figure 1) were stainedwith monoclonal anti-GC antibody (Abnova, Taipei, Taiwan) and sheep polyclonal anti-α-synuclein (1:400) (ABR, Rockford, IL). Immunofluorescent staining was followed by SudanBlack staining to quench autofluorescence [24]. Sudan Black did not affect the distribution orintensity of GC staining in LBs and LNs in subjects with GBA mutations. LAMP-1 positive,perikaryal amorphous inclusions still persisted after Sudan quenching. LAMP1 (purple), GC(green) and α-synuclein (red). DAPI (blue) was used as a nuclear counterstain. Scale bar =10microns (EPS 18,440 KB)

Figure S2

Immunofluorescent staining using rabbit polyclonal anti-GC (R386) antibody. BothGC positive and negative (arrow) α-synuclein pathology are present in the same field. GC (red)and α-synuclein (green). DAPI (blue) was used as a nuclear counterstain. Scale bar=10 microns (EPS 6,173 KB)

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Goker-Alpan, O., Stubblefield, B.K., Giasson, B.I. et al. Glucocerebrosidase is present in α-synuclein inclusions in Lewy body disorders. Acta Neuropathol 120, 641–649 (2010). https://doi.org/10.1007/s00401-010-0741-7

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