Glucocerebrosidase, a new player changing the old rules in Lewy body diseases

Biological Chemistry

Volumn 394, Issue 7, 2013, Pages 807-818

  Yang, Na Young ^a   Lee, Yu Na ^a   Lee, He Jin ^a   Kim, Yoon Suk ^b   Lee, Seung Jae ^a  

^a Konkuk University   (South Korea)

^b Yonsei University Wonju   (South Korea)

Author keywords

synuclein; Gaucher disease; GBA1; Glycolipid; Lysosome; Parkinson's disease

Indexed keywords

1 METHYL 4 PHENYLPYRIDINIUM; 1,2,3,6 TETRAHYDRO 1 METHYL 4 PHENYLPYRIDINE; ALPHA SYNUCLEIN; AMYLOID; CARRIER PROTEIN; CATHEPSIN; CATHEPSIN B; CATHEPSIN D; GLUCOSYLCERAMIDASE; GLUCOSYLCERAMIDE; GLUCOSYLSPHINGOSINE; GLYCOLIPID; PARKIN; RAPAMYCIN; TRIACYLGLYCEROL LIPASE; UBIQUITIN; UBIQUITIN PROTEIN LIGASE E3; UNCLASSIFIED DRUG;

ALZHEIMER DISEASE; ASTROCYTOSIS; AUTOPHAGOSOME; AUTOPHAGY; AUTOSOMAL DOMINANT INHERITANCE; BODY POSTURE; BRADYKINESIA; BRAIN CELL; BRAIN REGION; CELL MEMBRANE PERMEABILITY; CELL MUTANT; CELL STRAIN HEK293; CHAPERONE-MEDIATED AUTOPHAGY; COGNITIVE DEFECT; DEGENERATIVE DISEASE; DIFFUSE LEWY BODY DISEASE; DOPAMINERGIC NERVE CELL; ENDOPLASMIC RETICULUM ASSOCIATED DEGRADATION; ENZYME ACTIVITY; EXOCYTOSIS; FRONTOTEMPORAL DEMENTIA; GAUCHER DISEASE; GENE EXPRESSION; GENE MUTATION; GLIOSIS; GM1 GANGLIOSIDOSIS; HUMAN; HUNTINGTON CHOREA; LEWY BODY; LIPID COMPOSITION; LIPIDOSIS; LYSOSOME STORAGE DISEASE; MACROAUTOPHAGY; MICROAUTOPHAGY; MOTOR DYSFUNCTION; MULTIVESICULAR BODY; MUSCLE RIGIDITY; MUTATION RATE; NERVE CELL; NEURODEGENERATION WITH BRAIN IRON ACCUMULATION; NEUROPATHOLOGY; NIEMANN PICK DISEASE; PARKINSON DISEASE; PARKINSONISM; PC12 CELL; PHOSPHOLIPID METABOLISM; PRIORITY JOURNAL; PROTEIN FOLDING; RECESSIVE INHERITANCE; REVIEW; SHY DRAGER SYNDROME; SYNAPSE VESICLE; SYNAPTOSOME; TAUOPATHY; TREMOR;

ALPHA-SYNUCLEIN; GAUCHER DISEASE; GLUCOSYLCERAMIDASE; GLYCOLIPIDS; HUMANS; LEWY BODY DISEASE; LYSOSOMES; MUTATION;

EID: 84882262391     PISSN: 14316730     EISSN: 14374315     Source Type: Journal    
DOI: 10.1515/hsz-2012-0322     Document Type: Review

References (95)

1. Aharon-Peretz, J., Rosenbaum, H., and Gershoni-Baruch, R. (2004). Mutations in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews. N. Engl. J. Med. 351, 1972-1977.
2. Alcalay, R.N., Caccappolo, E., Mejia-Santana, H., Tang, M-., Rosado, L., Orbe Reilly, M., Ruiz, D., Ross, B., Verbitsky, M., Kisselev, S., et al. (2012). Cognitive performance of GBA mutation carriers with early-onset PD: the CORE-PD study. Neurology 78, 1434-1440.
3. Alonso-Canovas, A., Katschnig, P., Tucci, A., Carecchio, M., Wood, N.W., Edwards, M., Martinez Castrillo, J.C., Burke, D., Heales, S., and Bhatia, K.P. (2010). Atypical parkinsonism with apraxia and supranuclear gaze abnormalities in type 1 Gaucher disease. Expanding the spectrum: case report and literature review. Mov. Disord. 25, 1506-1509.
4. Alvarez-Erviti, L., Seow, Y., Schapira, A.H., Gardiner, C., Sargent, I.L., Wood, M.J., and Cooper, J.M. (2011). Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission. Neurobiol. Dis. 42, 360-367.
5. Auluck, P.K., Caraveo, G., and Lindquist, S. (2010). alpha-Synuclein: membrane interactions and toxicity in Parkinson's disease. Annu. Rev. Cell Dev. Biol. 26, 211-233.
6. Bahr, B.A. and Bendiske, J. (2002). The neuropathogenic contributions of lysosomal dysfunction. J. Neurochem. 83, 481-489.
7. Balducci, C., Pierguidi, L., Persichetti, E., Parnetti, L., Sbaragli, M., Tassi, C., Orlacchio, A., Calabresi, P., Beccari, T., and Rossi, A. (2007). Lysosomal hydrolases in cerebrospinal fluid from subjects with Parkinson's disease. Mov. Disord. 22, 1481-1484.
8. Bendikov-Bar, I., Ron, I., Filocamo, M., and Horowitz, M. (2011). Characterization of the ERAD process of the L444P mutant glucocerebrosidase variant. Blood Cells Mol. Dis. 46, 4-10.
9. Biegstraaten, M., van Schaik, I.N., Aerts, J.M., and Hollak, C.E. (2008).'Non-neuronopathic' Gaucher disease reconsidered. Prevalence of neurological manifestations in a Dutch cohort of type I Gaucher disease patients and a systematic review of the literature. J. Inherit. Metab. Dis. 31, 337-349.
10. Biegstraaten, M., van Schaik, I.N., Aerts, J.M., Langeveld, M., Mannens, M.M., Bour, L.J., Sidransky, E., Tayebi, N., Fitzgibbon, E., and Hollak, C.E. (2011). A monozygotic twin pair with highly discordant Gaucher phenotypes. Blood Cells Mol. Dis. 46, 39-41.
11. Braak, H. and Del Tredici, K. (2008). Invited Article: Nervous system pathology in sporadic Parkinson disease. Neurology 70, 1916-1925.
12. Bras, J., Singleton, A., Cookson, M.R., and Hardy, J. (2008). Emerging pathways in genetic Parkinson's disease: potential role of ceramide metabolism in Lewy body disease. FEBS J. 275, 5767-5773.
13. Brockmann, K., Hilker, R., Pilatus, U., Baudrexel, S., Srulijes, K., Magerkurth, J., Hauser, A.K., Schulte, C., Csoti, I., Merten, C.D., et al. (2012). GBA-associated PD. Neurodegeneration, altered membrane metabolism, and lack of energy failure. Neurology 79, 213-220.
14. Capablo, J.L., Saenz de Cabezon, A., Fraile, J., Alfonso, P., Pocovi, M., and Giraldo, P. (2008). Neurological evaluation of patients with Gaucher disease diagnosed as type 1. J. Neurol. Neurosurg. Psychiatry 79, 219-222.
15. Ciechanover, A. and Brundin, P. (2003). The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg. Neuron 40, 427-446.
16. Clark, L.N., Ross, B.M., Wang, Y., Mejia-Santana, H., Harris, J., Louis, E.D., Cote, L.J., Andrews, H., Fahn, S., Waters, C., et al. (2007). Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease. Neurology 69, 1270-1277.
17. Clark, L.N., Kartsaklis, L.A., Wolf Gilbert, R., Dorado, B., Ross, B.M., Kisselev, S., Verbitsky, M., Mejia-Santana, H., Cote, L.J., Andrews, H., et al. (2009). Association of glucocerebrosidase mutations with dementia with lewy bodies. Arch. Neurol. 66, 578-583.
18. Cullen, V., Sardi, S.P., Ng, J., Xu, Y.H., Sun, Y., Tomlinson, J.J., Kolodziej, P., Kahn, I., Saftig, P., Woulfe, J., et al. (2011). Acid beta-glucosidase mutants linked to Gaucher disease, Parkinson disease, and Lewy body dementia alter α -synuclein processing. Ann. Neurol. 69, 940-953.
19. Danzer, K.M., Ruf, W.P., Putcha, P., Joyner, D., Hashimoto, T., Glabe, C., Hyman, B.T., and McLean, P.J. (2011). Heat-shock protein 70 modulates toxic extracellular α -synuclein oligomers and rescues trans-synaptic toxicity. FASEB J. 25, 326-336.
20. Danzer, K.M., Kranich, L.R., Ruf, W.P., Cagsal-Getkin, O., Winslow, A.R., Zhu, L., Vanderburg, C.R., and McLean, P.J. (2012). Exosomal cell-to-cell transmission of α synuclein oligomers. Mol. Neurodegener. 7, 42.
21. de Rijk, M.C., Launer, L.J., Berger, K., Breteler, M.M., Dartigues, J.F., Baldereschi, M., Fratiglioni, L., Lobo, A., Martinez-Lage, J., Trenkwalder, C., et al. (2000). Prevalence of Parkinson's disease in Europe: a collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology 54, S21-23.
22. Dehay, B., Bove, J., Rodriguez-Muela, N., Perier, C., Recasens, A., Boya, P., and Vila, M. (2010). Pathogenic lysosomal depletion in Parkinson's disease. J. Neurosci. 30, 12535-12544.
23. Desplats, P., Lee, H.J., Bae, E.J., Patrick, C., Rockenstein, E., Crews, L., Spencer, B., Masliah, E., and Lee, S.J. (2009). Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α -synuclein. Proc. Natl. Acad. Sci. USA 106, 13010-13015.
24. Emmanouilidou, E., Melachroinou, K., Roumeliotis, T., Garbis, S.D., Ntzouni, M., Margaritis, L.H., Stefanis, L., and Vekrellis, K. (2010). Cell-produced α -synuclein is secreted in a calciumdependent manner by exosomes and impacts neuronal survival. J. Neurosci. 30, 6838-6851.
25. Farrer, M.J. (2006). Genetics of Parkinson disease: paradigm shifts and future prospects. Nat. Rev. Genet. 7, 306-318.
26. Farrer, M.J., Williams, L.N., Algom, A.A., Kachergus, J., Hulihan, M.M., Ross, O.A., Rajput, A., Papapetropoulos, S., Mash, D.C., and Dickson, D.W. (2009). Glucosidase- β variations and Lewy body disorders. Parkinsonism Relat. Disord. 15, 414-416.
27. Fortin, D.L., Troyer, M.D., Nakamura, K., Kubo, S., Anthony, M.D., and Edwards, R.H. (2004). Lipid rafts mediate the synaptic localization of α -synuclein. J. Neurosci. 24, 6715-6723.
28. Futerman, A.H., Sussman, J.L., Horowitz, M., Silman, I., and Zimran, A. (2004). New directions in the treatment of Gaucher disease. Trends. Pharmacol. Sci. 25, 147-151.
29. Galvin, J.E., Lee, V.M., and Trojanowski, J.Q. (2001). Synucleinopathies: clinical and pathological implications. Arch. Neurol. 58, 186-190.
30. Gegg, M.E., Burke, D., Heales, S.J., Cooper, J.M., Hardy, J., Wood, N.W., and Schapira, A.H. (2012). Glucocerebrosidase deficiency in substantia nigra of Parkinson disease brains. Ann. Neurol. 72, 455-463.
31. Goker-Alpan, O., Stubblefield, B.K., Giasson, B.I., and Sidransky, E. (2010). Glucocerebrosidase is present in α -synuclein inclusions in Lewy body disorders. Acta. Neuropathol. 120, 641-649.
32. Goker-Alpan, O., Schiffmann, R., LaMarca, M.E., Nussbaum, R.L., McInerney-Leo, A., and Sidransky. E. (2004). Parkinsonism among Gaucher disease carriers. J. Med. Genet. 41, 937-940.
33. Goker-Alpan, O., Lopez, G., Vithayathil, J., Davis, J., Hallett, M., and Sidransky, E. (2008). The spectrum of parkinsonian manifestations associated with glucocerebrosidase mutations. Arch. Neurol. 65, 1353-1357.
34. Goker-Alpan, O., Hruska, K.S., Orvisky, E., Kishnani, P.S., Stubblefield, B.K., Schiffmann, R., and Sidransky, E. (2005). Divergent phenotypes in Gaucher disease implicate the role of modifiers. J. Med. Genet. 42, e37.
35. Goker-Alpan, O., Giasson, B.I., Eblan, M.J., Nguyen, J., Hurtig, H.I., Lee, V.M., Trojanowski, J.Q., and Sidransky, E. (2006). Glucocerebrosidase mutations are an important risk factor for Lewy body disorders. Neurology 67, 908-910.
36. Halperin, A., Elstein, D., and Zimran, A. (2006). Increased incidence of Parkinson disease among relatives of patients with Gaucher disease. Blood Cells Mol. Dis. 36, 426-428.
37. Hansen, C., Angot, E., Bergstrom, A.L., Steiner, J.A., Pieri, L., Paul, G., Outeiro, T.F., Melki, R., Kallunki, P., Fog, K., et al. (2011). α -Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J. Clin. Invest. 121, 715-725.
38. Hein, L.K., Meikle, P.J., Hopwood, J.J., and Fuller, M. (2007). Secondary sphingolipid accumulation in a macrophage model of Gaucher disease. Mol. Genet. Metab. 92, 336-345.
39. Hein, L.K., Duplock, S., Hopwood, J.J., and Fuller, M. (2008). Lipid composition of microdomains is altered in a cell model of Gaucher disease. J. Lipid. Res. 49, 1725-1734.
40. Horowitz, M. and Ron, I. (2009). Interaction between parkin and glucocerebrosidase: a possible link between Parkinson disease and Gaucher disease. Mol. Genet. Metab. 96, S27 - S27.
41. Hruska, K.S., LaMarca, M.E., Scott, C.R., and Sidransky, E. (2008). Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA). Hum. Mutat. 29, 567-583.
42. Jamrozik, Z., Lugowska, A., Slawek, J., and Kwiecinski, H. (2010). Glucocerebrosidase mutations p.L444P and p.N370S are not associated with multisystem atrophy, progressive supranuclear palsy and corticobasal degeneration in Polish patients. J. Neurol. 257, 459-460.
43. Jang, A., Lee, H.J., Suk, J.E., Jung, J.W., Kim, K.P., and Lee, S.J. (2010). Non-classical exocytosis of α -synuclein is sensitive to folding states and promoted under stress conditions. J. Neurochem. 113, 1263-1274.
44. Jeyakumar, M., Williams, I., Smith, D., Cox, T.M., and Platt, F.M. (2009). Critical role of iron in the pathogenesis of the murine gangliosidoses. Neurobiol. Dis. 34, 406-416.
45. Jmoudiak, M. and Futerman, A.H. (2005). Gaucher disease: pathological mechanisms and modern management. Br. J. Haematol. 129, 178-188.
46. Kubo, S., Nemani, V.M., Chalkley, R.J., Anthony, M.D., Hattori, N., Mizuno, Y., Edwards, R.H., and Fortin, D.L. (2005). A combinatorial code for the interaction of α -synuclein with membranes. J. Biol. Chem. 280, 31664-31672.
47. Lansbury, P.T. and Lashuel, H.A. (2006). A century-old debate on protein aggregation and neurodegeneration enters the clinic. Nature 443, 774-779.
48. Lee, H.J., Patel, S., and Lee, S.J. (2005). Intravesicular localization and exocytosis of α -synuclein and its aggregates. J. Neurosci. 25, 6016-6024.
49. Lee, H.J., Khoshaghideh, F., Patel, S., and Lee, S.J. (2004). Clearance of α -synuclein oligomeric intermediates via the lysosomal degradation pathway. J. Neurosci. 24, 1888-1896.
50. Lee, H.J., Suk, J.E., Bae, E.J., Lee, J.H., Paik, S.R., and Lee, S.J. (2008). Assembly-dependent endocytosis and clearance of extracellular α -synuclein. Int. J. Biochem Cell Biol. 40, 1835-1849.
51. Lee, H.J., Suk, J.E., Patrick, C., Bae, E.J., Cho, J.H., Rho, S., Hwang, D., Masliah, E., and Lee, S.J. (2010). Direct transfer of α -synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J. Biol. Chem. 285, 9262-9272.
52. Lieberman, R.L., Wustman, B.A., Huertas, P., Powe, A.C, Jr., Pine, C.W., Khanna, R., Schlossmacher, M.G., Ringe, D., and Petsko, G.A. (2007). Structure of acid β -glucosidase with pharmacological chaperone provides insight into Gaucher disease. Nat. Chem. Biol. 3, 101-107.
53. Lilley, B.N. and Ploegh, H.L. (2004). A membrane protein required for dislocation of misfolded proteins from the ER. Nature 429, 834-840.
54. Lwin, A., Orvisky, E., Goker-Alpan, O., LaMarca, M.E., and Sidransky, E. (2004). Glucocerebrosidase mutations in subjects with parkinsonism. Mol. Genet. Metab. 81, 70-73.
55. Manning-Bog, A.B., Schule, B., and Langston, J.W. (2009). α -Synuclein-glucocerebrosidase interactions in pharmacological Gaucher models: a biological link between Gaucher disease and parkinsonism. Neurotoxicology 30, 1127-1132.
56. Martinez, Z., Zhu, M., Han, S., and Fink, A.L. (2007). GM1 specifically interacts with α -synuclein and inhibits fibrillation. Biochemistry 46, 1868-1877.
57. Mata, I.F., Samii, A., Schneer, S.H., Roberts, J.W., Griffith, A., Leis, B.C., Schellenberg, G.D., Sidransky, E., Bird, T.D., Leverenz, J.B., et al. (2008). Glucocerebrosidase gene mutations: a risk factor for Lewy body disorders. Arch. Neurol. 65, 379-382.
58. Mazzulli, J.R., Xu, Y.H., Sun, Y., Knight, A.L., McLean, P.J., Caldwell, G.A., Sidransky, E., Grabowski, G.A., and Krainc, D. (2011). Gaucher disease glucocerebrosidase and α -synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 146, 37-52.
59. Menzies, F.M., Ravikumar, B., and Rubinsztein, D.C. (2006). Protective roles for induction of autophagy in multiple proteinopathies. Autophagy 2, 224-225.
60. Mosca, M., Ceglie. A., and Ambrosone, L. (2011). Effect of membrane composition on lipid oxidation in liposomes. Chem. Phys. Lipids 164, 158-165.
61. Neudorfer, O., Giladi, N., Elstein, D., Abrahamov, A., Turezkite, T., Aghai, E., Reches, A., Bembi, B., and Zimran, A. (1996). Occurrence of Parkinson's syndrome in type I Gaucher disease. Q. J. Med. 89, 691-694.
62. Neumann, J., Bras, J., Deas, E., O'Sullivan, S.S., Parkkinen, L., Lachmann, R.H., Li, A., Holton, J., Guerreiro, R., Paudel, R., et al. (2009). Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease. Brain 132, 1783-1794.
63. O'Donnell, V.B., Eiserich, J.P., Chumley, P.H., Jablonsky, M.J., Krishna, N.R., Kirk, M., Barnes, S., Darley-Usmar, V.M., and Freeman, B.A. (1999). Nitration of unsaturated fatty acids by nitric oxide-derived reactive nitrogen species peroxynitrite, nitrous acid, nitrogen dioxide, and nitronium ion. Chem. Res. Toxicol. 12, 83-92.
64. Orvisky, E., Park, J.K., LaMarca, M.E., Ginns, E.I., Martin, B.M., Tayebi, N., and Sidransky, E. (2002). Glucosylsphingosine accumulation in tissues from patients with Gaucher disease: correlation with phenotype and genotype. Mol. Genet. Metab. 76, 262-270.
65. Pacheco, C.D., Kunkel, R., and Lieberman, A.P. (2007). Autophagy in Niemann-Pick C disease is dependent upon Beclin-1 and responsive to lipid trafficking defects. Hum. Mol. Genet. 16, 1495-1503.
66. Pan, T., Kondo, S., Le, W., and Jankovic, J. (2008). The role of autophagy-lysosome pathway in neurodegeneration associated with Parkinson's disease. Brain 131, 1969-1978.
67. Parnetti, L., Balducci, C., Pierguidi, L., De Carlo, C., Peducci, M., D'Amore, C., Padiglioni, C., Mastrocola, S., Persichetti, E., Paciotti, S., et al. (2009). Cerebrospinal fluid beta-glucocerebrosidase activity is reduced in dementia with Lewy bodies. Neurobiol. Dis. 34, 484-486.
68. Pastores, G.M. (1997). Gaucher's Disease. Pathological features. Baillieres Clin. Haematol. 10, 739-749.
69. Pennelli, N., Scaravilli, F., and Zacchello, F. (1969). The morphogenesis of Gaucher cells investigated by electron microscopy. Blood 34, 331-347.
70. Perrin, R.J., Woods, W.S., Clayton, D.F., and George, J.M. (2000). Interaction of human α -synuclein and Parkinson's disease variants with phospholipids. Structural analysis using site-directed mutagenesis. J. Biol. Chem. 275, 34393-34398.
71. Ron, I. and Horowitz, M. (2005). ER retention and degradation as the molecular basis underlying Gaucher disease heterogeneity. Hum. Mol. Genet. 14, 2387-2398.
72. Sardi, S.P., Clarke, J., Viel, C., Chan, M., Tamsett, T.J., Treleaven, C.M., Bu, J., Sweet, L., Passini, M.A., Dodge, J.C., et al. (2013). Augmenting CNS glucocerebrosidase activity as a therapeutic strategy for parkinsonism and other Gaucher-related synucleinopathies. Proc. Natl. Acad. Sci. USA 110, 3537-3542.
73. Sarkar, S., Perlstein, E.O., Imarisio, S., Pineau, S., Cordenier, A., Maglathlin, R.L., Webster, J.A., Lewis, T.A., O'Kane, C.J., Schreiber, S.L., et al. (2007). Small molecules enhance autophagy and reduce toxicity in Huntington's disease models. Nat. Chem. Biol. 3, 331-338.
74. Sawkar, A.R., Schmitz, M., Zimmer, K.P., Reczek, D., Edmunds, T., Balch, W.E., and Kelly, J.W. (2006). Chemical chaperones and permissive temperatures alter localization of Gaucher disease associated glucocerebrosidase variants. ACS Chem. Biol. 1, 235-251.
75. Scott, D.C. and Schekman, R. (2008). Role of Sec61p in the ER-associated degradation of short-lived transmembrane proteins. J. Cell Biol. 181, 1095-1105.
76. Segarane, B., Li, A., Paudel, R., Scholz, S., Neumann, J., Lees, A., Revesz, T., Hardy, J., Mathias, C.J., Wood, N.W., et al. (2009). Glucocerebrosidase mutations in 108 neuropathologically confirmed cases of multiple system atrophy. Neurology 72, 1185-1186.
77. Settembre, C., Fraldi, A., Jahreiss, L., Spampanato, C., Venturi, C., Medina, D., de Pablo, R., Tacchetti, C., Rubinsztein, D.C., and Ballabio, A. (2008). A block of autophagy in lysosomal storage disorders. Hum. Mol. Genet. 17, 119-129.
78. Shults, C.W. (2006). Lewy bodies. Proc. Natl. Acad. Sci. USA 103, 1661-1668.
79. Sidransky, E. and Lopez, G. (2012). The link between the GBA gene and parkinsonism. Lancet Neurol. 11, 986-998.
80. Sidransky, E., Nalls, M.A., Aasly, J.O., Aharon-Peretz, J., Annesi, G., Barbosa, E.R., Bar-Shira, A., Berg, D., Bras, J., Brice, A., et al. (2009). Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N. Engl. J. Med. 361, 1651-1661.
81. Sun, Y., Liou, B., Ran, H., Skelton, M.R., Williams, M.T., Vorhees, C.V., Kitatani, K., Hannun, Y.A., Witte, D.P., Xu, Y.H., et al. (2010). Neuronopathic Gaucher disease in the mouse: viable combined selective saposin C deficiency and mutant glucocerebrosidase (V394L) mice with glucosylsphingosine and glucosylceramide accumulation and progressive neurological deficits. Hum. Mol. Genet. 19, 1088-1097.
82. Takamura, A., Higaki, K., Kajimaki, K., Otsuka, S., Ninomiya, H., Matsuda, J., Ohno, K., Suzuki, Y., and Nanba, E. (2008). Enhanced autophagy and mitochondrial aberrations in murine G M1 -gangliosidosis. Biochem. Biophys. Res. Commun. 367, 616-622.
83. Tsuang, D., Leverenz, J.B., Lopez, O.L., Hamilton, R.L., Bennett, D.A., Schneider, J.A., Buchman, A.S., Larson, E.B., Crane, P.K., Kaye, J.A., et al. (2012). GBA mutations increase risk for Lewy body disease with and without Alzheimer disease pathology. Neurology 79, 1944-1950.
84. Tuite, P.J. and Krawczewski, K. (2007). Parkinsonism: a review-ofsystems approach to diagnosis. Semin. Neurol. 27, 113-122.
85. van Ham, T.J., Thijssen, K.L., Breitling, R., Hofstra, R.M., Plasterk, R.H., and Nollen, E.A. (2008). C. elegans model identifies genetic modifiers of α -synuclein inclusion formation during aging. PLoS Genet. 4, e1000027.
86. Vitner, E.B., Dekel, H., Zigdon, H., Shachar, T., Farfel-Becker, T., Eilam, R., Karlsson, S., and Futerman, A.H. (2010). Altered expression and distribution of cathepsins in neuronopathic forms of Gaucher disease and in other sphingolipidoses. Hum. Mol. Genet. 19, 3583-3590.
87. Volpicelli-Daley, L.A., Luk, K.C., Patel, T.P., Tanik, S.A., Riddle, D.M., Stieber, A., Meaney, D.F., Trojanowski, J.Q., and Lee, V.M. (2011). Exogenous α -synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 72, 57-71.
88. Wakabayashi, K., Tanji, K., Mori, F., and Takahashi, H. (2007). The Lewy body in Parkinson's disease: molecules implicated in the formation and degradation of α -synuclein aggregates. Neuropathology 27, 494-506.
89. Walkley, S.U. (2004). Secondary accumulation of gangliosides in lysosomal storage disorders. Semin. Cell Dev. Biol. 15, 433-444.
90. Wei, J., Fujita, M., Nakai, M., Waragai, M., Sekigawa, A., Sugama, S., Takenouchi, T., Masliah, E., and Hashimoto, M. (2009). Protective role of endogenous gangliosides for lysosomal pathology in a cellular model of synucleinopathies. Am. J. Pathol. 174, 1891-1909.
91. Wong, K., Sidransky, E., Verma, A., Mixon, T., Sandberg, G.D., Wakefield, L.K., Morrison, A., Lwin, A., Colegial, C., Allman, J.M., et al. (2004). Neuropathology provides clues to the pathophysiology of Gaucher disease. Mol. Genet. Metab. 82, 192-207.
92. Xia, Q., Liao, L., Cheng, D., Duong, D.M., Gearing, M., Lah, J.J., Levey, A.I., and Peng, J. (2008). Proteomic identification of novel proteins associated with Lewy bodies. Front Biosci. 13, 3850-3856.
93. Yap, T.L., Velayati, A., Sidransky, E., and Lee, J.C. (2013). Membrane-bound alpha-synuclein interacts with glucocerebrosidase and inhibits enzyme activity. Mol. Genet. Metab. 108, 56-64.
94. Yap, T.L., Gruschus, J.M., Velayati, A., Westbroek, W., Goldin, E., Moaven, N., Sidransky, E., and Lee, J.C. (2011). Alpha-synuclein interacts with Glucocerebrosidase providing a molecular link between Parkinson and Gaucher diseases. J. Biol. Chem. 286, 28080-28088.
95. Ye, Y., Shibata, Y., Yun, C., Ron, D., and Rapoport, T.A. (2004). A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol. Nature 429, 841-847.