Neurochemical Research

, Volume 36, Issue 10, pp 1939–1944 | Cite as

Decreased Expression of Lysosomal Alpha-Galactosiase A Gene in Sporadic Parkinson’s Disease

  • Guanghua Wu
  • Jian Huang
  • Xungang Feng
  • Aimei Zhang
  • Jifeng Li
  • Shuchao Pang
  • Kejin Gu
  • Haixin Dong
  • Junping Zhang
  • Huijie Gao
  • Bo Yan
Original Paper


Parkinson’s disease (PD) is a progressive neurodegenerative disease. To date, the causal genes and variants associated with sporadic PD are largely unknown. Accumulating evidence demonstrates that autophagy delivers alpha-syncuclein proteins to lysosome for degradation and dysfunctional autophagy is involved in the PD pathogenesis. We have previously screened a group of lysosomal hydrolases and found that alpha-galactosidase A (GLA) activity is significantly decreased in the peripheral leukocytes of sporadic PD patients. In this study, GLA transcript and protein levels were semi-quantitatively examined. The GLA transcript (P = 0.020) and protein (P = 0.027) levels in the peripheral leukocytes of sporadic PD patients were significantly decreased, compared to age- and sex-matched healthy controls. Furthermore, decreased GLA gene expression levels were strongly associated with sporadic PD (OR 3.33, 95%CI 1.17–9.52, P = 0.024). Therefore, our data suggest that insufficient GLA activity may contribute to the pathogenesis of sporadic PD. The underlying molecular mechanisms remain to be determined.


Parkinson’s disease Lysosome Alpha-galactosidase A Gene expression Leukocytes 


  1. 1.
    Bras JM, Singleton A (2009) Genetic susceptibility in Parkinson’s disease. Biochim Biophys Acta 1792:597–603PubMedGoogle Scholar
  2. 2.
    Gasser T (2009) Mendelian forms of Parkinson’s disease. Biochim Biophys Acta 1792:587–596PubMedGoogle Scholar
  3. 3.
    Lesage S, Brice A (2009) Parkinson’s disease: from monogenic forms to genetic susceptibility factors. Hum Mol Genet 18(R1):R48–R59PubMedCrossRefGoogle Scholar
  4. 4.
    Xie W, Wan OW, Chung KK (2010) New insights into the role of mitochondrial dysfunction and protein aggregation in Parkinson’s disease. Biochim Biophys Acta 1802:935–941PubMedGoogle Scholar
  5. 5.
    Bandopadhyay R, de Belleroche J (2010) Pathogenesis of Parkinson’s disease: emerging role of molecular chaperones. Trends Mol Med 16:27–36PubMedCrossRefGoogle Scholar
  6. 6.
    Cookson MR, Bandmann O (2010) Parkinson’s disease: insights from pathways. Hum Mol Genet 19(R1):R21–R27PubMedCrossRefGoogle Scholar
  7. 7.
    Hardy J (2010) Genetic analysis of pathways to Parkinson disease. Neuron 68:201–206PubMedCrossRefGoogle Scholar
  8. 8.
    Spillantini MG, Schmidt ML, Lee VM et al (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840PubMedCrossRefGoogle Scholar
  9. 9.
    Waxman EA, Giasson BI (2009) Molecular mechanisms of alpha-synuclein neurodegeneration. Biochim Biophys Acta 1792:616–624PubMedGoogle Scholar
  10. 10.
    Simón-Sánchez J, Schulte C, Bras JM et al (2009) Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet 41:1308–1312PubMedCrossRefGoogle Scholar
  11. 11.
    Maraganore DM, de Andrade M, Elbaz A et al (2006) Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. JAMA 296:661–670PubMedCrossRefGoogle Scholar
  12. 12.
    Winkler S, Hagenah J, Lincoln S et al (2007) alpha-Synuclein and Parkinson disease susceptibility. Neurology 69:1745–1750PubMedCrossRefGoogle Scholar
  13. 13.
    Eriksen JL, Przedborski S, Petrucelli L (2005) Gene dosage and pathogenesis of Parkinson’s disease. Trends Mol Med 11:91–96PubMedCrossRefGoogle Scholar
  14. 14.
    Levine B, Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132:27–42PubMedCrossRefGoogle Scholar
  15. 15.
    Levine B, Klionsky DJ (2004) Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 6:463–477PubMedCrossRefGoogle Scholar
  16. 16.
    Banerjee R, Beal MF, Thomas B (2010) Autophagy in neurodegenerative disorders: pathogenic roles and therapeutic implications. Trends Neurosci 33:541–549PubMedCrossRefGoogle Scholar
  17. 17.
    Pan T, Kondo S, Le W et al (2008) The role of autophagy-lysosome pathway in neurodegeneration associated with Parkinson’s disease. Brain 131(Pt 8):1969–1978PubMedCrossRefGoogle Scholar
  18. 18.
    Wong E, Cuervo AM (2010) Autophagy gone awry in neurodegenerative diseases. Nat Neurosci 13:805–811PubMedCrossRefGoogle Scholar
  19. 19.
    Cuervo AM, Stefanis L, Fredenburg R et al (2004) Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305:1292–1295PubMedCrossRefGoogle Scholar
  20. 20.
    Lee HJ, Khoshaghideh F, Patel S et al (2004) Clearance of alpha-synuclein oligomeric intermediates via the lysosomal degradation pathway. J Neurosci 24:1888–1896PubMedCrossRefGoogle Scholar
  21. 21.
    Mak SK, McCormack AL, Manning-Bog AB et al (2010) Lysosomal degradation of alpha-synuclein in vivo. J Biol Chem 285:13621–13629PubMedCrossRefGoogle Scholar
  22. 22.
    Vogiatzi T, Xilouri M, Vekrellis K et al (2008) Wild type alpha-synuclein is degraded by chaperone-mediated autophagy and macroautophagy in neuronal cells. J Biol Chem 283:23542–23556PubMedCrossRefGoogle Scholar
  23. 23.
    Webb JL, Ravikumar B, Atkins J et al (2003) Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem 278:25009–25013PubMedCrossRefGoogle Scholar
  24. 24.
    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 351:1972–1977PubMedCrossRefGoogle Scholar
  25. 25.
    Ramirez A, Heimbach A, Gründemann J et al (2006) Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet 38:1184–1191PubMedCrossRefGoogle Scholar
  26. 26.
    Saito Y, Suzuki K, Hulette CM et al (2004) Aberrant phosphorylation of alpha-synuclein in human Niemann-Pick type C1 disease. J Neuropathol Exp Neurol 63:323–328PubMedGoogle Scholar
  27. 27.
    Suzuki K, Iseki E, Katsuse O et al (2003) Neuronal accumulation of alpha- and beta-synucleins in the brain of a GM2 gangliosidosis mouse model. Neuroreport 14:551–554PubMedCrossRefGoogle Scholar
  28. 28.
    Suzuki K, Iseki E, Togo T et al (2007) Neuronal and glial accumulation of alpha- and beta-synucleins in human lipidoses. Acta Neuropathol 114:481–489PubMedCrossRefGoogle Scholar
  29. 29.
    Desnick RJ, Ioannou YA, Eng CM (2001) α-Galactosidase A deficiency: Fabry disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Kinzler KE, Vogelstein B (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 3733–3774Google Scholar
  30. 30.
    Wu G, Yan B, Wang X et al (2008) Decreased activities of lysosomal acid alpha-D-galactosidase A in the leukocytes of sporadic Parkinson’s disease. J Neurol Sci 271:168–173PubMedCrossRefGoogle Scholar
  31. 31.
    Jeyakumar M, Dwek RA, Butters TD et al (2005) Storage solutions: treating lysosomal disorders of the brain. Nat Rev Neurosci 6:713–725PubMedGoogle Scholar
  32. 32.
    Fukuda T, Ewan L, Bauer M et al (2006) Dysfunction of endocytic and autophagic pathways in a lysosomal storage disease. Ann Neurol 59:700–708PubMedCrossRefGoogle Scholar
  33. 33.
    Koike M, Shibata M, Waguri S et al (2005) Participation of autophagy in storage of lysosomes in neurons from mouse models of neuronal ceroid-lipofuscinoses (Batten disease). Am J Pathol 167:1713–1728PubMedCrossRefGoogle Scholar
  34. 34.
    Settembre C, Fraldi A, Jahreiss L et al (2008) A block of autophagy in lysosomal storage disorders. Hum Mol Genet 17:119–129PubMedCrossRefGoogle Scholar
  35. 35.
    Tanaka Y, Guhde G, Suter A et al (2000) Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice. Nature 406:902–906PubMedCrossRefGoogle Scholar
  36. 36.
    Vergarajauregui S, Connelly PS, Daniels MP et al (2008) Autophagic dysfunction in mucolipidosis type IV patients. Hum Mol Genet 17:2723–2737PubMedCrossRefGoogle Scholar
  37. 37.
    Settembre C, Fraldi A, Rubinsztein DC et al (2008) Lysosomal storage diseases as disorders of autophagy. Autophagy 4:113–114PubMedGoogle Scholar
  38. 38.
    Chévrier M, Brakch N, Lesueur C et al (2010) Autophagosome maturation is impaired in Fabry disease. Autophagy 6:589–599CrossRefGoogle Scholar
  39. 39.
    Hara T, Nakamura K, Matsui M et al (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441:885–889PubMedCrossRefGoogle Scholar
  40. 40.
    Komatsu M, Waguri S, Chiba T et al (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441:880–884PubMedCrossRefGoogle Scholar
  41. 41.
    Ballabio A, Gieselmann V (2009) Lysosomal disorders: from storage to cellular damage. Biochim Biophys Acta 1793:684–696PubMedCrossRefGoogle Scholar
  42. 42.
    Eckhardt M (2010) Pathology and current treatment of neurodegenerative sphingolipidoses. Neuromolecular Med 12:362–382PubMedCrossRefGoogle Scholar
  43. 43.
    Yu RK, Nakatani Y, Yanagisawa M (2009) The role of glycosphingolipid metabolism in the developing brain. J Lipid Res 50(Suppl):S440–S445PubMedCrossRefGoogle Scholar
  44. 44.
    Wei J, Fujita M, Nakai M et al (2009) Protective role of endogenous gangliosides for lysosomal pathology in a cellular model of synucleinopathies. Am J Pathol 174:1891–1909PubMedCrossRefGoogle Scholar
  45. 45.
    Wu G, Lu ZH, Kulkarni N et al (2011) Mice lacking major brain gangliosides develop Parkinsonism. Neurochem Res (in press)Google Scholar
  46. 46.
    Futerman AH, van Meer G (2004) The cell biology of lysosomal storage disorders. Nat Rev Mol Cell Biol 5:554–565PubMedCrossRefGoogle Scholar
  47. 47.
    Meikle PJ, Hopwood JJ, Clague AE et al (1999) Prevalence of lysosomal storage disorders. JAMA 281:249–254PubMedCrossRefGoogle Scholar
  48. 48.
    Spada M, Pagliardini S, Yasuda M et al (2006) High incidence of later-onset fabry disease revealed by newborn screening. Am J Hum Genet 79:31–40PubMedCrossRefGoogle Scholar
  49. 49.
    Zarate YA, Hopkin RJ (2008) Fabry’s disease. Lancet 372:1427–1435PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Guanghua Wu
    • 1
    • 2
  • Jian Huang
    • 2
  • Xungang Feng
    • 3
  • Aimei Zhang
    • 3
  • Jifeng Li
    • 3
  • Shuchao Pang
    • 2
  • Kejin Gu
    • 3
  • Haixin Dong
    • 4
  • Junping Zhang
    • 2
  • Huijie Gao
    • 5
  • Bo Yan
    • 2
  1. 1.Division of Cardiac SurgeryJining Medical College Affiliated Hospital, Jining Medical CollegeJiningChina
  2. 2.Shandong Provincial Key Laboratory of Cardiac Disease Diagnosis and TreatmentJining Medical College Affiliated Hospital, Jining Medical CollegeJiningChina
  3. 3.Division of NeurologyJining Medical College Affiliated Hospital, Jining Medical CollegeJiningChina
  4. 4.Division of Experimental MedicineJining Medical College Affiliated Hospital, Jining Medical CollegeJiningChina
  5. 5.Department of ImmunologyJining Medical CollegeJiningChina

Personalised recommendations