The contribution of mutant GBA to the development of Parkinson disease in Drosophila

Human Molecular Genetics

Volumn 25, Issue 13, 2016, Pages 2712-2727

  Maor, Gali ^a   Cabasso, Or ^a   Krivoruk, Olga ^a   Rodriguez, Joe ^a   Steller, Hermann ^a   Segal, Daniel ^b   Horowitz, Mia ^a  

^a ROCKEFELLER UNIVERSITY   (United States)

^b TEL AVIV UNIVERSITY   (Israel)

Author keywords

[No Author keywords available]

Indexed keywords

AMBROXOL; CHAPERONE; CONDURITOL B EPOXIDE; ENDONUCLEASE; EPOXIDE; GLUCOSYLCERAMIDASE; MESSENGER RNA; SPHINGOLIPID; TYROSINE 3 MONOOXYGENASE; UNCLASSIFIED DRUG;

ANIMAL CELL; ARTICLE; CLIMBING; CONFOCAL MICROSCOPY; CONTROLLED STUDY; DISEASE CARRIER; DOPAMINERGIC NERVE CELL; DROSOPHILA MELANOGASTER; ENDOPLASMIC RETICULUM STRESS; GAUCHER DISEASE; GENE EXPRESSION; GENE FREQUENCY; GENE INSERTION; GENE MUTATION; HUMAN; HUMAN CELL; IMMUNOFLUORESCENCE; MOUSE; NONHUMAN; PARKINSON DISEASE; PARKINSONISM; PLASMID; REAL TIME POLYMERASE CHAIN REACTION; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; RNA SPLICING; SURVIVAL ANALYSIS; THIN LAYER CHROMATOGRAPHY; TRANSGENE; UNFOLDED PROTEIN RESPONSE; WESTERN BLOTTING; WILD TYPE; ANIMAL; DISEASE MODEL; ENDOPLASMIC RETICULUM; GENETICS; HETEROZYGOTE; METABOLISM; MUTATION; PHYSIOLOGY;

AMBROXOL; ANIMALS; DISEASE MODELS, ANIMAL; DOPAMINERGIC NEURONS; DROSOPHILA MELANOGASTER; ENDOPLASMIC RETICULUM; GAUCHER DISEASE; GLUCOSYLCERAMIDASE; HETEROZYGOTE; HUMANS; MUTATION; PARKINSON DISEASE; UNFOLDED PROTEIN RESPONSE;

EID: 85016007737     PISSN: 09646906     EISSN: 14602083     Source Type: Journal    
DOI: 10.1093/hmg/ddw129     Document Type: Article

References (101)

1. Beutler, E. (1980) Gaucher's disease. Compr Ther, 6, 65-68.
2. Beutler, E. (1999) Gaucher disease. Arch. Intern. Med., 159, 881-882.
3. Brady, R.O., Kanfer, J.N. and Shapiro, D. (1965) Metabolism of Glucocerebrosides. Ii. Evidence of an Enzymatic Deficiency in Gaucher's Disease. Biochem. Biophys. Res. Commun., 18, 221-225.
4. 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.
5. Tsuji, S., Martin, B.M., Barranger, J.A., Stubblefield, B.K., LaMarca, M.E. and Ginns, E.I. (1988) Genetic heterogeneity in type 1 Gaucher disease: multiple genotypes in Ashkenazic and non-Ashkenazic individuals. Proc. Natl. Acad. Sci. U S A, 85, 2349-2352.
6. Tsuji, S., Choudary, P.V., Martin, B.M., Stubblefield, B.K., Mayor, J.A., Barranger, J.A. and Ginns, E.I. (1987) A mutation in the human glucocerebrosidase gene in neuronopathic Gaucher's disease. N. Engl. J. Med., 316, 570-575.
7. Beutler, E., Gelbart, T., Kuhl, W., Sorge, J. and West, C. (1991) Identification of the second common Jewish Gaucher disease mutation makes possible population-based screening for the heterozygous state. Proc. Natl. Acad. Sci. U S A, 88, 10544-10547.
8. Benyair, R., Ron, E. and Lederkremer, G.Z. (2011) Protein quality control, retention, and degradation at the endoplasmic reticulum. Int. Rev. Cell. Mol. Biol., 292, 197-280.
9. Beutler, E. and Kuhl, W. (1986) Glucocerebrosidase processing in normal fibroblasts and in fibroblasts from patients with type I, type II, and type III Gaucher disease. Proc. Natl. Acad. Sci. U S A, 83, 7472-7474.
10. Erickson, A.H., Ginns, E.I. and Barranger, J.A. (1985) Biosynthesis of the lysosomal enzyme glucocerebrosidase. J. Biol. Chem., 260, 14319-14324.
11. Jonsson, L.M., Murray, G.J., Sorrell, S.H., Strijland, A., Aerts, J.F., Ginns, E.I., Barranger, J.A., Tager, J.M. and Schram, A.W. (1987) Biosynthesis and maturation of glucocerebrosidase in Gaucher fibroblasts. Eur. J. Biochem., 164, 171-179.
12. Ron, I. and Horowitz, M. (2005) ER retention and degradation as the molecular basis underlying Gaucher disease heterogeneity. Hum. Mol. Genet., 14, 2387-2398.
13. Maor, G., Rencus-Lazar, S., Filocamo, M., Steller, H., Segal, D. and Horowitz, M. (2013) Unfolded protein response in Gaucher disease: from human to Drosophila. Orphanet. J. Rare Dis., 8, 140.
14. 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. Qjm, 89, 691-694.
15. Tayebi, N., Callahan, M., Madike, V., Stubblefield, B.K., Orvisky, E., Krasnewich, D., Fillano, J.J. and Sidransky, E. (2001) Gaucher disease and parkinsonism: a phenotypic and genotypic characterization. Mol. Genet. Metab., 73, 313-321.
16. Bembi, B., Zambito Marsala, S., Sidransky, E., Ciana, G., Carrozzi, M., Zorzon, M., Martini, C., Gioulis, M., Pittis, M.G. and Capus, L. (2003) Gaucher's disease with Parkinson disease: clinical and pathological aspects. Neurology, 61, 99-101.
17. Tayebi, N., Walker, J., Stubblefield, B., Orvisky, E., LaMarca, M.E., Wong, K., Rosenbaum, H., Schiffmann, R., Bembi, B. and Sidransky, E. (2003) Gaucher disease with parkinsonian manifestations: does glucocerebrosidase deficiency contribute to a vulnerability to parkinsonism? Mol. Genet. Metab., 79, 104-109.
18. Varkonyi, J., Rosenbaum, H., Baumann, N., MacKenzie, J.J., Simon, Z., Aharon-Peretz, J., Walker, J.M., Tayebi, N. and Sidransky, E. (2003) Gaucher disease associated with parkinsonism: four further case reports. Am. J. Med. Genet. A, 116A, 348-351.
19. Aharon-Peretz, J., Rosenbaum, H. and Gershoni-Baruch, R. (2004) Mutations in the glucocerebrosidase gene and Parkinson disease in Ashkenazi Jews. N. Engl. J. Med., 351, 1972-1977.
20. Sidransky, E. (2005) Gaucher disease and parkinsonism. Mol. Genet. Metab., 84, 302-304.
21. Hruska, K.S., Goker-Alpan, O. and Sidransky, E. (2006) Gaucher disease and the synucleinopathies. J. Biomed. Biotechnol., 2006, 78549.
22. Tan, E.K., Tong, J., Fook-Chong, S., Yih, Y., Wong, M.C., Pavanni, R. and Zhao, Y. (2007) Glucocerebrosidase mutations and risk of Parkinson disease in Chinese patients. Arch. Neurol., 64, 1056-1058.
23. 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 disease. N. Engl. J. Med., 361, 1651-1661.
24. Shulman, J.M., De Jager, P.L. and Feany, M.B. (2011) Parkinson disease: genetics and pathogenesis. Annu. Rev. Pathol., 6, 193-222.
25. Wang, M., Ye, R., Barron, E., Baumeister, P., Mao, C., Luo, S., Fu, Y., Luo, B., Dubeau, L., Hinton, D.R., et al. (2010) Essential role of the unfolded protein response regulator GRP78/BiP in protection from neuronal apoptosis. Cell Death Differ., 17, 488-498.
26. Stutzbach, L.D., Xie, S.X., Naj, A.C., Albin, R., Gilman, S., Lee, V.M., Trojanowski, J.Q., Devlin, B. and Schellenberg, G.D. (2013) The unfolded protein response is activated in disease-affected brain regions in progressive supranuclear palsy and Alzheimer's disease. Acta Neuropathol. Commun., 1, 31.
27. Forman, M.S., Lee, V.M. and Trojanowski, J.Q. (2003) 'Unfolding' pathways in neurodegenerative disease. Trends Neurosci., 26, 407-410.
28. Mercado, G., Valdes, P. and Hetz, C. (2013) An ERcentric view of Parkinson disease. Trends Mol. Med., 19, 165-175.
29. Varma, D. and Sen, D. (2015) Role of the unfolded protein response in the pathogenesis of Parkinson disease. Acta Neurobiol. Exp. (Wars), 75, 1-26.
30. Lu, B. and Vogel, H. (2009) Drosophila models of neurodegenerative diseases. Annu. Rev. Pathol., 4, 315-342.
31. Whitworth, A.J. (2011) Drosophila models of Parkinson disease. Adv. Genet., 73, 1-50.
32. West, R.J., Furmston, R., Williams, C.A. and Elliott, C.J. (2015) Neurophysiology of Drosophila models of Parkinson disease. Parkinsons Dis., 2015, 381281.
33. Rincon-Limas, D.E., Jensen, K. and Fernandez-Funez, P. (2012) Drosophila models of proteinopathies: the little fly that could. Curr. Pharm. Des., 18, 1108-1122.
34. Kaminker, J.S., Bergman, C.M., Kronmiller, B., Carlson, J., Svirskas, R., Patel, S., Frise, E., Wheeler, D.A., Lewis, S.E., Rubin, G.M., et al. (2002) The transposable elements of the Drosophila melanogaster euchromatin: a genomics perspective. Genome Biol., 3, RESEARCH0084.
35. Gokcezade, J., Sienski, G. and Duchek, P. (2014) Efficient CRISPR/Cas9 plasmids for rapid and versatile genome editing in Drosophila. G3 (Bethesda), 4, 2279-2282.
36. Bassett, A.R. and Liu, J.L. (2014) CRISPR/Cas9 and genome editing in Drosophila. J. Genet. Genomics, 41, 7-19.
37. Duffy, J.B. (2002) GAL4 system in Drosophila: a fly geneticist's Swiss army knife. Genesis, 34, 1-15.
38. Suzuki, T., Shimoda, M., Ito, K., Hanai, S., Aizawa, H., Kato, T., Kawasaki, K., Yamaguchi, T., Ryoo, H.D., Goto-Inoue, N., et al. (2013) Expression of human Gaucher disease gene GBA generates neurodevelopmental defects and ER stress in Drosophila eye. PLoS One, 8, e69147.
39. Mao, Z. and Davis, R.L. (2009) Eight different types of dopaminergic neurons innervate the Drosophila mushroom body neuropil: anatomical and physiological heterogeneity. Front. Neural Circuits, 3, 5.
40. Feany, M.B. and Bender, W.W. (2000) A Drosophila model of Parkinson disease. Nature, 404, 394-398.
41. Sawkar, A.R., Cheng, W.C., Beutler, E., Wong, C.H., Balch, W.E. and Kelly, J.W. (2002) Chemical chaperones increase the cellular activity of N370S beta-glucosidase: a therapeutic strategy for Gaucher disease. Proc. Natl. Acad. Sci. U S A, 99, 15428-15433.
42. Bendikov-Bar, I., Maor, G., Filocamo, M. and Horowitz, M. (2013) Ambroxol as a pharmacological chaperone for mutant glucocerebrosidase. Blood Cells Mol. Dis., 50, 141-145.
43. Zimran, A., Altarescu, G. and Elstein, D. (2013) Pilot study using ambroxol as a pharmacological chaperone in type 1 Gaucher disease. Blood Cells Mol. Dis., 50, 134-137.
44. McNeill, A., Magalhaes, J., Shen, C., Chau, K.Y., Hughes, D., Mehta, A., Foltynie, T., Cooper, J.M., Abramov, A.Y., Gegg, M., et al. (2014) Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells. Brain, 137, 1481-1495.
45. Mu, T.W., Ong, D.S., Wang, Y.J., Balch, W.E., Yates, J.R., 3rd, Segatori, L. and Kelly, J.W. (2008) Chemical and biological approaches synergize to ameliorate protein-folding diseases. Cell, 134, 769-781.
46. Araki, K. and Nagata, K. (2011) Protein folding and quality control in the ER. Cold Spring Harb. Perspect. Biol., 3, a007526.
47. Kalia, S.K., Kalia, L.V. and McLean, P.J. (2010) Molecular chaperones as rational drug targets for Parkinson disease therapeutics. CNS Neurol. Disord. Drug Targets, 9, 741-753.
48. 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 alphasynuclein processing. Ann. Neurol., 69, 940-953.
49. Cortez, L. and Sim, V. (2014) The therapeutic potential of chemical chaperones in protein folding diseases. Prion, 8,
50. Babajani, G., Tropak, M.B., Mahuran, D.J. and Kermode, A.R. (2012) Pharmacological chaperones facilitate the post-ER transport of recombinant N370S mutant betaglucocerebrosidase in plant cells: evidence that N370S is a folding mutant. Mol. Genet. Metab., 106, 323-329.
51. Maegawa, G.H., Tropak, M.B., Buttner, J.D., Rigat, B.A., Fuller, M., Pandit, D., Tang, L., Kornhaber, G.J., Hamuro, Y., Clarke, J.T., et al. (2009) Identification and characterization of ambroxol as an enzyme enhancement agent for Gaucher disease. J. Biol. Chem., 284, 23502-23516.
52. Sorge, J.A., West, C., Kuhl, W., Treger, L. and Beutler, E. (1987) The human glucocerebrosidase gene has two functional ATG initiator codons.Am. J. Hum. Genet., 41, 1016-1024.
53. Pasmanik-Chor, M., Elroy-Stein, O., Aerts, H., Agmon, V., Gatt, S. and Horowitz, M. (1996) Overexpression of human glucocerebrosidase containing different-sized leaders. Biochem. J., 317, 81-88.
54. Lesage, S., Anheim, M., Condroyer, C., Pollak, P., Durif, F., Dupuits, C., Viallet, F., Lohmann, E., Corvol, J.C., Honore, A., et al. (2011) Large-scale screening of the Gaucher's diseaserelated glucocerebrosidase gene in Europeans with Parkinson disease. Hum. Mol. Genet., 20, 202-210.
55. Gan-Or, Z., Giladi, N., Rozovski, U., Shifrin, C., Rosner, S., Gurevich, T., Bar-Shira, A. and Orr-Urtreger, A. (2008) Genotype-phenotype correlations between GBA mutations and Parkinson disease risk and onset. Neurology, 70, 2277-2283.
56. Ast, T., Michaelis, S. and Schuldiner, M. (2016) The Protease Ste24 Clears Clogged Translocons. Cell, 164, 103-114.
57. Welihinda, A.A., Tirasophon, W. and Kaufman, R.J. (1999) The cellular response to protein misfolding in the endoplasmic reticulum. Gene Expr., 7, 293-300.
58. Mendez, A.S., Alfaro, J., Morales-Soto, M.A., Dar, A.C., McCullagh, E., Gotthardt, K., Li, H., Acosta-Alvear, D., Sidrauski, C., Korennykh, A.V., et al. (2015) Endoplasmic reticulum stress-independent activation of unfolded protein response kinases by a small molecule ATP-mimic. Elife, 4,
59. Xie, W., Pariollaud, M., Wixted, W.E., Chitnis, N., Fornwald, J., Truong, M., Pao, C., Liu, Y., Ames, R.S., Callahan, J., et al. (2015) Identification and characterization of PERK activators by phenotypic screening and their effects on NRF2 activation. PLoS One, 10, e0119738.
60. 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.
61. Aharon-Peretz, J., Badarny, S., Rosenbaum, H. and Gershoni-Baruch, R. (2005) Mutations in the glucocerebrosidase gene and Parkinson disease: phenotype-genotype correlation. Neurology, 65, 1460-1461.
62. Sato, C., Morgan, A., Lang, A.E., Salehi-Rad, S., Kawarai, T., Meng, Y., Ray, P.N., Farrer, L.A., St George-Hyslop, P. and Rogaeva, E. (2005) Analysis of the glucocerebrosidase gene in Parkinson disease. Mov. Disord., 20, 367-370.
63. 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.
64. Wu, Y.R., Chen, C.M., Chao, C.Y., Ro, L.S., Lyu, R.K., Chang, K.H. and Lee-Chen, G.J. (2007) Glucocerebrosidase gene mutation is a risk factor for early onset of Parkinson disease among Taiwanese. J. Neurol. Neurosurg. Psychiatry, 78, 977-979.
65. Mitsui, J., Mizuta, I., Toyoda, A., Ashida, R., Takahashi, Y., Goto, J., Fukuda, Y., Date, H., Iwata, A., Yamamoto, M., et al. (2009) Mutations for Gaucher disease confer high susceptibility to Parkinson disease. Arch. Neurol., 66, 571-576.
66. Rosenbloom, B., Balwani, M., Bronstein, J.M., Kolodny, E., Sathe, S., Gwosdow, A.R., Taylor, J.S., Cole, J.A., Zimran, A. and Weinreb, N.J. (2011) The incidence of Parkinsonism in patients with type 1 Gaucher disease: data from the ICGG Gaucher Registry. Blood Cells Mol. Dis., 46, 95-102.
67. Beavan, M.S. and Schapira, A.H. (2013) Glucocerebrosidase mutations and the pathogenesis of Parkinson disease. Ann. Med., 45, 511-521.
68. Griffiths, A., Miller, J., Suzuki, D., Lewontin, R. and Gelbart, W. (2000) An Introduction to Genetic Analysis, W. H. Freeman, New York.
69. Gegg, M.E., Sweet, L., Wang, B.H., Shihabuddin, L.S., Sardi, S.P. and Schapira, A.H. (2015) No evidence for substrate accumulation in Parkinson brains with GBA mutations. Mov. Disord., 30, 1085-1089.
70. Tybulewicz, V.L., Tremblay, M.L., LaMarca, M.E., Willemsen, R., Stubblefield, B.K., Winfield, S., Zablocka, B., Sidransky, E., Martin, B.M., Huang, S.P., et al. (1992) Animal model of Gaucher's disease from targeted disruption of the mouse glucocerebrosidase gene. Nature, 357, 407-410.
71. Enquist, I.B., Nilsson, E., Ooka, A., Mansson, J.E., Olsson, K., Ehinger, M., Brady, R.O., Richter, J. and Karlsson, S. (2006) Effective cell and gene therapy in a murine model of Gaucher disease. Proc. Natl. Acad. Sci. U S A, 103, 13819-13824.
72. Mistry, P.K., Liu, J., Yang, M., Nottoli, T., McGrath, J., Jain, D., Zhang, K., Keutzer, J., Chuang, W.L., Mehal, W.Z., et al. (2010) Glucocerebrosidase gene-deficient mouse recapitulates Gaucher disease displaying cellular and molecular dysregulation beyond the macrophage. Proc. Natl. Acad. Sci. U S A, 107, 19473-19478.
73. Xu, Y.H., Reboulet, R., Quinn, B., Huelsken, J., Witte, D. and Grabowski, G.A. (2008) Dependence of reversibility and progression of mouse neuronopathic Gaucher disease on acid beta-glucosidase residual activity levels. Mol. Genet. Metab., 94, 190-203.
74. Beutler, E., Nguyen, N.J., Henneberger, M.W., Smolec, J.M., McPherson, R.A., West, C. and Gelbart, T. (1993) Gaucher disease: gene frequencies in the Ashkenazi Jewish population. Am. J. Hum. Genet., 52, 85-88.
75. Xu, Y.H., Quinn, B., Witte, D. and Grabowski, G.A. (2003) Viable mouse models of acid beta-glucosidase deficiency: the defect in Gaucher disease. Am. J. Pathol., 163, 2093-2101.
76. Mizukami, H., Mi, Y., Wada, R., Kono, M., Yamashita, T., Liu, Y., Werth, N., Sandhoff, R., Sandhoff, K. and Proia, R.L. (2002) Systemic inflammation in glucocerebrosidasedeficient mice with minimal glucosylceramide storage. J. Clin. Invest., 109, 1215-1221.
77. Sardi, S.P., Singh, P., Cheng, S.H., Shihabuddin, L.S. and Schlossmacher, M.G. (2012) Mutant GBA1 expression and synucleinopathy risk: first insights from cellular and mouse models. Neurodegener. Dis., 10, 195-202.
78. Xu, Y.H., Sun, Y., Ran, H., Quinn, B., Witte, D. and Grabowski, G.A. (2011) Accumulation and distribution of alpha-synuclein and ubiquitin in the CNS of Gaucher disease mouse models. Mol. Genet. Metab., 102, 436-447.
79. Sardi, S.P., Clarke, J., Kinnecom, C., Tamsett, T.J., Li, L., Stanek, L.M., Passini, M.A., Grabowski, G.A., Schlossmacher, M.G., Sidman, R.L., et al. (2011) CNS expression of glucocerebrosidase corrects alpha-synuclein pathology and memory in a mouse model of Gaucher-related synucleinopathy. Proc. Natl. Acad. Sci. U S A, 108, 12101-12106.
80. 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 alphasynuclein form a bidirectional pathogenic loop in synucleinopathies. Cell, 146, 37-52.
81. Fishbein, I., Kuo, Y.M., Giasson, B.I. and Nussbaum, R.L. (2014) Augmentation of phenotype in a transgenic Parkinson mouse heterozygous for a Gaucher mutation. Brain, 137, 3235-3247.
82. Clark, I.E., Dodson, M.W., Jiang, C., Cao, J.H., Huh, J.R., Seol, J.H., Yoo, S.J., Hay, B.A. and Guo, M. (2006) Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature, 441, 1162-1166.
83. Ng, C.H., Mok, S.Z., Koh, C., Ouyang, X., Fivaz, M.L., Tan, E.K., Dawson, V.L., Dawson, T.M., Yu, F. and Lim, K.L. (2009) Parkin protects against LRRK2 G2019S mutant-induced dopaminergic neurodegeneration in Drosophila. J. Neurosci., 29, 11257-11262.
84. Pesah, Y., Pham, T., Burgess, H., Middlebrooks, B., Verstreken, P., Zhou, Y., Harding, M., Bellen, H. and Mardon, G. (2004) Drosophila parkin mutants have decreased mass and cell size and increased sensitivity to oxygen radical stress. Development, 131, 2183-2194.
85. Moore, D.J., Dawson, V.L. and Dawson, T.M. (2006) Lessons from Drosophila models of DJ-1 deficiency. Sci. Aging Knowledge Environ., 2006, pe2.
86. Bonini, N.M. (2002) Chaperoning brain degeneration. Proc. Natl. Acad. Sci. U S A, 99(suppl. 4), 16407-16411.
87. McNeill, A. (2015) Lysosomal dysfunction in Parkinson disease. Brain, 138, e339.
88. Schondorf, D.C., Aureli, M., McAllister, F.E., Hindley, C.J., Mayer, F., Schmid, B., Sardi, S.P., Valsecchi, M., Hoffmann, S., Schwarz, L.K., et al. (2014) iPSC-derived neurons from GBA1-associated Parkinson disease patients show autophagic defects and impaired calcium homeostasis. Nat. Commun., 5, 4028.
89. Awad, O., Sarkar, C., Panicker, L.M., Miller, D., Zeng, X., Sgambato, J.A., Lipinski, M.M. and Feldman, R.A. (2015) Altered TFEB-mediated lysosomal biogenesis in Gaucher disease iPSC-derived neuronal cells. Hum. Mol. Genet., 24, 5775-5788.
90. Du, T.T., Wang, L., Duan, C.L., Lu, L.L., Zhang, J.L., Gao, G., Qiu, X.B., Wang, X.M. and Yang, H. (2015) GBA deficiency promotes SNCA/alpha-synuclein accumulation through autophagic inhibition by inactivated PPP2A. Autophagy, 11, 1803-1820.
91. Matus, S., Lisbona, F., Torres, M., Leon, C., Thielen, P. and Hetz, C. (2008) The stress rheostat: an interplay between the unfolded protein response (UPR) and autophagy in neurodegeneration. Curr. Mol. Med., 8, 157-172.
92. Jenner, P. and Olanow, C.W. (1998) Understanding cell death in Parkinson disease. Ann. Neurol., 44, S72-S84.
93. Puschmann, A., Bhidayasiri, R. and Weiner, W.J. (2012) Synucleinopathies from bench to bedside. Parkinsonism Relat. Disord., 18(Suppl. 1), S24-S27.
94. Gasser, T. (1998) Genetics of Parkinson disease. Ann. Neurol., 44, S53-S57.
95. Choi, J.H., Stubblefield, B., Cookson, M.R., Goldin, E., Velayati, A., Tayebi, N. and Sidransky, E. (2011) Aggregation of alpha-synuclein in brain samples from subjects with glucocerebrosidase mutations. Mol. Genet. Metab., 104, 185-188.
96. Goker-Alpan, O., Stubblefield, B.K., Giasson, B.I. and Sidransky, E. (2010) Glucocerebrosidase is present in alphasynuclein inclusions in Lewy body disorders. Acta Neuropathol., 120, 641-649.
97. 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.
98. Manning-Bog, A.B., Schule, B. and Langston, J.W. (2009) Alpha-synuclein-glucocerebrosidase interactions in pharmacological Gaucher models: a biological link between Gaucher disease and parkinsonism. Neurotoxicology, 30, 1127-1132.
99. Velayati, A., Yu, W.H. and Sidransky, E. (2010) The role of glucocerebrosidase mutations in Parkinson disease and Lewy body disorders. Curr. Neurol. Neurosci. Rep., 10, 190-198.
100. Liu, Z., Wang, X., Yu, Y., Li, X., Wang, T., Jiang, H., Ren, Q., Jiao, Y., Sawa, A., Moran, T., et al. (2008) A Drosophila model for LRRK2-linked parkinsonism. Proc. Natl. Acad. Sci. U S A, 105, 2693-2698.
101. Folch, J., Lees, M. and Sloane Stanley, G.H. (1957) A simple method for the isolation and purification of total lipides from animal tissues. J. Biol. Chem., 226, 497-509.