Abstract
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.
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References
Bras JM, Singleton A (2009) Genetic susceptibility in Parkinson’s disease. Biochim Biophys Acta 1792:597–603
Gasser T (2009) Mendelian forms of Parkinson’s disease. Biochim Biophys Acta 1792:587–596
Lesage S, Brice A (2009) Parkinson’s disease: from monogenic forms to genetic susceptibility factors. Hum Mol Genet 18(R1):R48–R59
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 1802:935–941
Bandopadhyay R, de Belleroche J (2010) Pathogenesis of Parkinson’s disease: emerging role of molecular chaperones. Trends Mol Med 16:27–36
Cookson MR, Bandmann O (2010) Parkinson’s disease: insights from pathways. Hum Mol Genet 19(R1):R21–R27
Hardy J (2010) Genetic analysis of pathways to Parkinson disease. Neuron 68:201–206
Spillantini MG, Schmidt ML, Lee VM et al (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840
Waxman EA, Giasson BI (2009) Molecular mechanisms of alpha-synuclein neurodegeneration. Biochim Biophys Acta 1792:616–624
Simón-Sánchez J, Schulte C, Bras JM et al (2009) Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet 41:1308–1312
Maraganore DM, de Andrade M, Elbaz A et al (2006) Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. JAMA 296:661–670
Winkler S, Hagenah J, Lincoln S et al (2007) alpha-Synuclein and Parkinson disease susceptibility. Neurology 69:1745–1750
Eriksen JL, Przedborski S, Petrucelli L (2005) Gene dosage and pathogenesis of Parkinson’s disease. Trends Mol Med 11:91–96
Levine B, Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132:27–42
Levine B, Klionsky DJ (2004) Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 6:463–477
Banerjee R, Beal MF, Thomas B (2010) Autophagy in neurodegenerative disorders: pathogenic roles and therapeutic implications. Trends Neurosci 33:541–549
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):1969–1978
Wong E, Cuervo AM (2010) Autophagy gone awry in neurodegenerative diseases. Nat Neurosci 13:805–811
Cuervo AM, Stefanis L, Fredenburg R et al (2004) Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305:1292–1295
Lee HJ, Khoshaghideh F, Patel S et al (2004) Clearance of alpha-synuclein oligomeric intermediates via the lysosomal degradation pathway. J Neurosci 24:1888–1896
Mak SK, McCormack AL, Manning-Bog AB et al (2010) Lysosomal degradation of alpha-synuclein in vivo. J Biol Chem 285:13621–13629
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 283:23542–23556
Webb JL, Ravikumar B, Atkins J et al (2003) Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem 278:25009–25013
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
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 38:1184–1191
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 63:323–328
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 14:551–554
Suzuki K, Iseki E, Togo T et al (2007) Neuronal and glial accumulation of alpha- and beta-synucleins in human lipidoses. Acta Neuropathol 114:481–489
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 3733–3774
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 271:168–173
Jeyakumar M, Dwek RA, Butters TD et al (2005) Storage solutions: treating lysosomal disorders of the brain. Nat Rev Neurosci 6:713–725
Fukuda T, Ewan L, Bauer M et al (2006) Dysfunction of endocytic and autophagic pathways in a lysosomal storage disease. Ann Neurol 59:700–708
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 167:1713–1728
Settembre C, Fraldi A, Jahreiss L et al (2008) A block of autophagy in lysosomal storage disorders. Hum Mol Genet 17:119–129
Tanaka Y, Guhde G, Suter A et al (2000) Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice. Nature 406:902–906
Vergarajauregui S, Connelly PS, Daniels MP et al (2008) Autophagic dysfunction in mucolipidosis type IV patients. Hum Mol Genet 17:2723–2737
Settembre C, Fraldi A, Rubinsztein DC et al (2008) Lysosomal storage diseases as disorders of autophagy. Autophagy 4:113–114
Chévrier M, Brakch N, Lesueur C et al (2010) Autophagosome maturation is impaired in Fabry disease. Autophagy 6:589–599
Hara T, Nakamura K, Matsui M et al (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441:885–889
Komatsu M, Waguri S, Chiba T et al (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441:880–884
Ballabio A, Gieselmann V (2009) Lysosomal disorders: from storage to cellular damage. Biochim Biophys Acta 1793:684–696
Eckhardt M (2010) Pathology and current treatment of neurodegenerative sphingolipidoses. Neuromolecular Med 12:362–382
Yu RK, Nakatani Y, Yanagisawa M (2009) The role of glycosphingolipid metabolism in the developing brain. J Lipid Res 50(Suppl):S440–S445
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 174:1891–1909
Wu G, Lu ZH, Kulkarni N et al (2011) Mice lacking major brain gangliosides develop Parkinsonism. Neurochem Res (in press)
Futerman AH, van Meer G (2004) The cell biology of lysosomal storage disorders. Nat Rev Mol Cell Biol 5:554–565
Meikle PJ, Hopwood JJ, Clague AE et al (1999) Prevalence of lysosomal storage disorders. JAMA 281:249–254
Spada M, Pagliardini S, Yasuda M et al (2006) High incidence of later-onset fabry disease revealed by newborn screening. Am J Hum Genet 79:31–40
Zarate YA, Hopkin RJ (2008) Fabry’s disease. Lancet 372:1427–1435
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This study is supported by National Natural Science Foundation of China (No. 30771190) and Jining Medical College Affiliated Hospital.
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Wu, G., Huang, J., Feng, X. et al. Decreased Expression of Lysosomal Alpha-Galactosiase A Gene in Sporadic Parkinson’s Disease. Neurochem Res 36, 1939–1944 (2011). https://doi.org/10.1007/s11064-011-0516-0
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DOI: https://doi.org/10.1007/s11064-011-0516-0