Glucocerebrosidase mutations and the pathogenesis of Parkinson disease

Annals of Medicine

Volumn 45, Issue 8, 2013, Pages 511-521

  Beavan, Michelle S ^a   Schapira, Anthony H V ^a  

^a UNIVERSITY COLLEGE LONDON   (United Kingdom)

Author keywords

Gaucher disease; Glucocerebrosidase; Parkinson disease

Indexed keywords

ALPHA SYNUCLEIN; GLUCOSYLCERAMIDASE; LEVODOPA; PARKIN; PARVOVIRUS VECTOR; PROTEASOME; RECOMBINANT ENZYME; RECOMBINANT GLUCOSYLCERAMIDASE; UBIQUITIN; UNCLASSIFIED DRUG;

AGE DISTRIBUTION; ALZHEIMER DISEASE; AUTOPHAGY; AUTOSOMAL RECESSIVE INHERITANCE; CLINICAL FEATURE; COGNITIVE DEFECT; DIFFUSE LEWY BODY DISEASE; DISEASE ASSOCIATION; ENDOPLASMIC RETICULUM ASSOCIATED DEGRADATION; ENDOPLASMIC RETICULUM STRESS; ENZYME ACTIVITY; ETHNICITY; GAUCHER DISEASE; GENE MUTATION; GENETIC PREDISPOSITION; GENETIC RISK; HETEROZYGOTE; HOMOZYGOTE; HUMAN; LEWY BODY; LIPID METABOLISM; MITOPHAGY; NEUROIMAGING; NEUROPATHOLOGY; NONHUMAN; ONSET AGE; PARKINSON DISEASE; PARKINSONISM; PATHOGENESIS; PENETRANCE; PHENOTYPE; POSITRON EMISSION TOMOGRAPHY; PRIORITY JOURNAL; REVIEW; SEX DIFFERENCE; SHY DRAGER SYNDROME; SINGLE PHOTON EMISSION COMPUTER TOMOGRAPHY; UNFOLDED PROTEIN RESPONSE; VIRAL GENE DELIVERY SYSTEM;

GAUCHER DISEASE; GENETIC MARKERS; GENETIC PREDISPOSITION TO DISEASE; GLUCOSYLCERAMIDASE; HETEROZYGOTE; HUMANS; MUTATION; PARKINSON DISEASE; PHENOTYPE; TOMOGRAPHY, EMISSION-COMPUTED;

EID: 84887574376     PISSN: 07853890     EISSN: 13652060     Source Type: Journal    
DOI: 10.3109/07853890.2013.849003     Document Type: Review

References (132)

1. Gaucher PCE. De l epithelioma primitif de la rate, hypertrophieidiopathique de la rate sans leucemie . Academic thesis . 1882 . Paris, France
2. Grabowski GA. Phenotype, diagnosis and treatment of Gaucher s disease. Lancet. 2008; 372: 1263-71
3. R aghavan S S, T opol J , K olodny E H. L eukocyte beta-glucosidase in homozygotes and heterozygotes for Gaucher disease . Am J Hum Genet. 1980 ; 32 : 158-73 . (Pubitemid 10105547)
4. Beutler E, Grabowski GA. Gaucher disease. Th e metabolic and molecular bases of inherited disease. 2001; 2: 3635-68
5. Cox TM, Schofi eld JP. Gaucher s disease: clinical features and natural history . Baillieres Clin Haematol. 1997; 10: 657-89 (Pubitemid 28022202)
6. Zimran A, Gelbart T, Westwood B, Grabowski GA, Beutler E. High frequency of the Gaucher disease mutation at nucleotide 1226 among Ashkenazi Jews . Am J Hum Genet. 1991 ; 49 : 855-9 . (Pubitemid 21891732)
7. Sidransky E. Gaucher disease: complexity in a simple disorder. Mol Genet Metab. 2004; 83: 6-15 (Pubitemid 39311276)
8. Lachmann RH, Grant IR, Halsall D, Cox TM. Twin pairs showing discordance of phenotype in adult Gaucher s disease . QJM. 2004 ; 97 : 199-204 . (Pubitemid 38489159)
9. Biegstraaten M, van Schaik IN, Aerts JM, Langeveld M, Mannens MM, Bour LJ , et al . A monozygotic twin pair with highly discordant Gaucher phenotypes. Blood Cells Mol Dis. 2011; 46: 39-41
10. Bendikov-Bar I, Maor G, Filocamo M, Horowitz M. Ambroxol as a pharmacological chaperone for mutant glucocerebrosidase . Blood Cells Mol Dis. 2013 ; 50 : 141-5 .
11. Sun Y, Liou B, Xu YH, Quinn B, Zhang W, Hamler R, et al. Ex vivo and in vivo eff ects of isofagomine on acid -glucosidase variants and substrate levels in Gaucher disease. J Biol Chem. 2012; 287: 4275-87
12. Hruska KS, LaMarca ME, Scott CR, Sidransky E. Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA) . Hum Mutat. 2008 ; 29 : 567-83 . (Pubitemid 351614580)
13. Mitsui J, Mizuta I, Toyoda A, Ashida R, Takahashi Y, Goto J, et al. Mutations for Gaucher disease confer high susceptibility to Parkinson disease. Arch Neurol. 2009; 66: 571-6
14. H uang C L, W u-Chou Y H, L ai S C, C hang H C, Y eh T H, W eng Y H, et al . Contribution of glucocerebrosidase mutation in a large cohort of sporadic Parkinson s disease in Taiwan . Eur J Neurol. 2011 ; 18 : 1227-32 .
15. V an Bogaert L F. U n cas de maladie de Gaucher de l a dulte avec syndrome de Raynaud, pigmentation, et rigidite du type extra-pyramidal aux members inferieurs. Ann Med. 1939; 45: 57-70.
16. Turpin JC , Dubois G , Brice A , Masson M , Nadaud 16. MC, Boutry JM, et al . Parkinsonian symptomatology in a patient with type I (adult) Gaucher s disease. Lipid storage disorders . New York: Plenum Press ; 1987 . p. 103-9 .
17. Sack GH. Clinical diversity in Gaucher s disease. Johns Hopkins Med J. 1980 ; 146 : 166-70 .
18. Tayebi N, Walker J, Stubblefi eld B, Orvisky E, LaMarca ME, Wong K, et al . Gaucher disease with parkinsonism manifestations: does glucocerebrosidase defi ciency contribute to a vulnerability to parkinsonism? Mol Genet Metab. 2003; 79: 104-9 (Pubitemid 36693928)
19. Bembi B, Zambito Marsala S, Sidransky E, Ciana G, Carrozzi M, Zorzon M, et al . Gaucher s disease with Parkinson s disease. Clinical and pathological aspects. Neurology. 2003; 61: 99-101 (Pubitemid 36818755)
20. Goker-Alpan O, Schiff mann R, LaMarca ME, Nussbaum RL, McInerney-Leo A, Sidransky E . Parkinsonism among Gaucher disease carriers . J Med Genet. 2004 ; 41 : 937-40 .
21. Halperin A, Elstein D, Zimran A. Increased incidence of Parkinson disease among relatives of patients with Gaucher disease . Blood Cells Mol Dis. 2006; 36: 426-8 (Pubitemid 43776190)
22. Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER , et al . Multicenter analysis of glucocerebrosidase mutations in Parkinson s disease. N Engl J Med. 2009; 361: 1651-61
23. Mata IF, Samii A, Schneer SH, Roberts JW, Griffi th A, Leis BC, et al. Glucocerebrosidase gene mutations-A risk factor for Lewy body disorders. Arch Neurol. 2008; 65: 379-82 (Pubitemid 351398524)
24. Lwin A, Orvisky E, Goker-Alpan O, LaMarca ME, Sidransky E. Glucocerebrosidase mutations in subjects with parkinsonism . Mol Genet Metab. 2004; 81: 70-3 (Pubitemid 38064435)
25. Duran R, Mencacci NE, Angeli AV, Shoai M, Deas E, Houlden H. Th e glucocerebrosidase E326K variant predisposes to Parkinson s disease, but does not cause Gaucher s disease. Mov Disord. 2013; 28: 232-6
26. Chetrit EB, Alcalay RN, Steiner-Birmanns B, Altarescu G, Phillips M, Elstein D , Zimran A . Phenotype in patients with Gaucher disease and Parkinson disease. Blood Cells Mol Dis. 2013; 50: 218-21
27. R osenbloom B , B alwani M , B ronstein J M, K olodny E , S athe S , Gwosdow AR , et al . Th e incidence of Parkinsonism in patients with type 1 Gaucher disease: data from the ICGG Gaucher Registry . Blood Cells Mol Dis. 2011 ; 46 : 95-102 .
28. Bultron G, Kacena K, Pearson D, Boxer M, Yang R, Sathe S, et al. Th e risk of Parkinson s disease in type 1 Gaucher disease . J Inherit Metab Dis. 2010; 33: 167-73
29. Rana HQ, Balwani M, Bier L, Alcalay RN. Age-specifi c Parkinson disease risk in GBA mutation carriers: information for genetic counseling . Genet Med. 2013; 15: 146-9
30. Anheim, M, Elbaz A, Lesage S, Durr A, Condroyer C, Viallet F, et al. ; French Parkinson Disease Genetic Group Penetrance of Parkinson disease in glucocerebrosidase gene mutation carriers . Neurology. 2012 ; 78 : 417-20 .
31. McNeill A, Duran R, Hughes DA, Mehta A, Schapira AH. A clinical and family history study of Parkinson s disease in heterozygous glucocerebrosidase mutation carriers . J Neurol Neurosurg Psychiatry. 2012 ; 83 : 853-4 .
32. Goker-Alpan O, Giasson BI, Eblan MJ, Nguyen J, Hurtig HI, Lee VM, et al . Glucocerebrosidase mutations are an important risk factor for Lewy body disorders. Neurology. 2006; 67: 908-10 (Pubitemid 44394221)
33. Nalls MA, Duran R, Lopez G, Kurzawa-Akanbi M, McKeith IG, Chinnery PF , et al . A multicenter study of glucocerebrosidase mutations in dementia with Lewy bodies . JAMA Neurol. 2013 ; 15 : 1-9 .
34. Segarane B, Li A, Paudel R, Scholz S, Neumann J, Lees A, et al. Glucocerebrosidase mutations in 108 neuropathologically confi rmed cases of multiple systems atrophy . Neurology. 2009; 72: 1185-6
35. Jamrozik Z, Lugowska A, Slawek J, Kwiecinski H. Glucocerebrosidase mutations p.L444P and p.N370S are not associated with multisystem atrophy, progressive supranuclear palsy and corticobasal degeneration in Polish patients. J Neurol. 2010; 257: 459-60
36. Neumann J, Bras J, Deas E, O Sullivan SS, Parkkinen L, Lachmann RH, et al . Glucocerebrosidase mutations in clinical and pathologically proven Parkinson s disease. Brain. 2009; 132: 1783-94
37. G oker-Alpan O , L opez G , V ithayathil J , D avis J , H allett M , S idransky E . Th e spectrum of parkinsonian manifestations associated with glucocerebrosidase mutations. Arch Neurol. 2008; 65: 1353-7
38. Gan-Or Z, Giladi N, Orr-Urtreger A. Diff erential phenotype in Parkinson s disease patients with severe versus mild GBA mutations . Brain. 2009 ; 132 : e125 .
39. C lark L N, R oss B M, W ang Y , M ejia-Santana H , H arris J , L ouis E D, e t a l. Mutations in the glucocerebrosidase gene are associated with earlyonset Parkinson disease. Neurology. 2007; 69: 1270-7 (Pubitemid 47429028)
40. Neudorfer O, Giladi N, Elstein D, Abrahamov A, Turezkite T, Aghai E, et al . Occurrence of Parkinson s syndrome in type I Gaucher disease . QJM. 1996 ; 89 : 691-4 . (Pubitemid 26319021)
41. Set o -Salvia N, Pagonabarraga J, Houlden H, Pascual-Sedano B, Dols-Icardo O , Tucci A, et al . Glucocerebrosidase mutations confer a greater risk of dementia during Parkinson s disease course . Mov Disord. 2012; 27: 393-9
42. W inder-Rhodes S E, E vans J R, B an M , M ason S L, W illiams-Gray C H, Foltynie T , et al . Glucocerebrosidase mutations infl uence the natural history of Parkinson s disease in a community-based incident cohort . Brain. 2013 ; 136 : 392-9 .
43. Ziegler SG, Eblan MJ, Gutti U, Hruska KS, Stubblefi eld BK, Goker-Alpan O , et al . Glucocerebrosidase mutations in Chinese subjects from Taiwan with sporadic Parkinson disease . Mol Genet Metab. 2007 ; 91 : 195-200 . (Pubitemid 46765177)
44. Wong K, Sidransky E, Verma A, Mixon T, Sandberg GD, Wakefi eld LK, et al . Neuropathology provides clues to the pathophysiology of Gaucher disease. Mol Genet Metab. 2004; 82: 192-207 (Pubitemid 38952652)
45. Goker-Alpan O, Stubblefi eld BK, Giasson BI, Sidransky E. Glucocerebrosidase is present in -synuclein inclusions in Lewy body disorders. Acta Neuropathol. 2010; 120: 641-9
46. Alcalay RN, Caccappolo E, Mejia-Santana H, Tang M, Rosado L, Orbe Reilly M , et al . Cognitive performance of GBA mutation carriers with early-onset PD: the CORE-PD study . Neurology. 2012 ; 78 : 1434-40 .
47. Brockmann K, Srulijes K, Hauser AK, Schulte C, Csoti I, Gasser T, Berg D , . GBA-associated PD presents with nonmotor characteristics . Neurology. 2011; 77: 276-80
48. Clark LN, Kartsaklis LA, Wolf Gilbert R, Dorado B, Ross BM, Kisselev S, et al . Association of glucocerebrosidase mutations with dementia with Lewy bodies. Arch Neurol. 2009; 66: 578-83
49. P arkkinen L , N eumann J , O S ullivan S S, H olton J L, R evesz T , H ardy J , et al . Glucocerebrosidase mutations do not cause increased Lewy body pathology in Parkinson s disease. Mol Genet Metab. 2011; 103: 410-12
50. S ardi S P, C larke J , K innecom C , T amsett T J, L i L , S tanek L M, e t a l. C NS expression of glucocerebrosidase corrects alpha-synuclein pathology and memory in a mouse model of Gaucher-related synucleinopathy . Proc Natl Acad Sci U S A. 2011 ; 108 : 1210-16 .
51. Aharon-Peretz J, Rosenbaum H, Gershoni-Baruch R. Mutations in the glucocerebrosidase gene and Parkinson s disease in Ashkenazi Jews . N Engl J Med. 2004; 351: 1972-7 (Pubitemid 39447138)
52. Sato C, Morgan A, Lang AE, Salehi-Rad S, Kawarai T, Meng Y, et al. Analysis of the glucocerebrosidase gene in Parkinson s disease . Mov Disord. 2005; 20: 367-70 (Pubitemid 40613301)
53. Toft M, Pielsticker L, Ross OA, Aasly JO, Farrer MJ. Glucocerebrosidase gene mutations and Parkinson disease in the Norwegian population . Neurology. 2006; 66: 415-7 (Pubitemid 43739947)
54. Eblan MJ, Scholz S, Stubblefi eld B, Gutti U, Goker-Alpan O, Hruska KS , et al . Glucocerebrosidase mutations are not found in association with LRRK2 G2019S in subjects with parkinsonism . Neurosci Lett. 2006 ; 404 : 163-5 . (Pubitemid 44041786)
55. Tan EK, Tong J, Fook-Chong S, Yih Y, Wong MC, Pavanni R, et al. Glucocerebrosidase mutations and risk of Parkinson disease in Chinese patients. Arch Neurol. 2007; 64: 1056-8 (Pubitemid 47048012)
56. Wu YR, Chen CM, Chao CY, Ro LS, Lyu RK, Chang KH, et al. Glucocerebrosidase gene mutation is a risk factor for early onset of Parkinson disease among Taiwanese . J Neurol Neurosurg Psychiatry. 2007 ; 78 : 977-9 .
57. De Marco EV, Annesi G, Tarantino P, Rocca FE, Provenzano G, Civitelli D , et al . Glucocerebrosidase gene mutations are associated with Parkinson s disease in southern Italy . Mov Disord. 2008 ; 23 : 460-3 .
58. S pitz M , R ozenberg R , D a Veiga Pereira L , B arbosa E R. A ssociation between Parkinson s disease and glucocerebrosidase mutations in Brazil. Parkinsonism Relat Disord. 2008; 14: 58-62
59. Gan-Or Z, Giladi N, Rozovski U, Shifrin C, Rosner S, Gurevich T, et al. Genotype-phenotype correlations between GBA mutations and Parkinson disease risk and onset. Neurology. 2008; 70: 2277-83
60. Bras JM, Singleton A. Genetic susceptibility in Parkinson s disease. Biochim Biophys Acta. 2009; 1792: 597-603
61. Kalinderi K, Bostantjopoulou S, Paisan-Ruiz C, Katsarou Z, Hardy J , Fidani L . Complete screening for glucocerebrosidase mutations in Parkinson disease patients from Greece . Neurosci Lett. 2009 ; 452 : 87-9 .
62. Nichols WC, Pankratz N, Marek DK, Pauciulo MW, Elsaesser VE, Halter CA, et al.; Parkinson Study Group-PROGENI Investigators. Mutations in GBA are associated with familial Parkinson disease susceptibility and age at onset. Neurology. 2009; 72: 310-16
63. A, Usenko T, Drosdova A, Zakharchuk A, et al . Glucocerebrosidase gene mutations are associated with Parkinson s disease in Russia. Mov Disord. 2012; 27: 158-9
64. Saunders-Pullman R, Hagenah J, Dhawan V, Stanley K, Pastores G, Sathe S, et al . Gaucher disease ascertained through a Parkinson s center: imaging and clinical characterization . Mov Disord. 2010 ; 25 : 1364-72 .
65. Mao XY, Burgunder JM, Zhang ZJ, An XK, Zhang JH, Yang Y, et al. Association between GBA L444P mutation and sporadic Parkinson s disease from mainland China. Neurosci Lett. 2010; 469: 256-9
66. Sun QY, Guo JF, Wang L, et al. Glucocerebrosidase gene L444P mutation is a risk factor for Parkinson s disease in Chinese population . Mov Disord. 2010; 25: 1005-11
67. Hu FY, Xi J, Guo J, Yu LH, Liu L, He XH, et al. Association of the glucocerebrosidase N370S allele with Parkinson s disease in two separate Chinese Han populations of mainland China . Eur J Neurol. 2010 ; 17 : 1476-8 .
68. Lesage S, Condroyer C, Hecham N, Anheim M, Belarbi S, Lohman E, et al .; French Parkinson Disease Genetic Group . Mutations in the glucocerebrosidase gene confer a risk for Parkinson disease in north Africa. Neurology. 2011; 76: 301-3
69. Noreau A, Riviere JB, Diab S, Dion PA, Panisset M, Soland V, et al. Glucocerebrosidase mutations in a French-Canadian Parkinson s disease cohort . Can J Neurol Sci. 2011; 38: 772-3
70. Lesage S, Anheim M, Condroyer C, Pollak P, Durif F, Dupuits C, et al .; French Parkinson s Disease Genetics Study Group . Large-scale screening of the Gaucher s disease-related glucocerebrosidase gene in Europeans with Parkinson s disease . Hum Mol Genet. 2011 ; 20 : 202-10 .
71. Choi JM, Kim WC, Lyoo CH, Kang SY, Lee PH, Baik JS, et al. Association of mutations in the glucocerebrosidase gene with Parkinson disease in a Korean population . Neurosci Lett. 2012 ; 514 : 12-15 .
72. Zhang X, Bao QQ, Zhuang XS, Gan SR, Zhao D, Liu Y, et al. Association of common variants in the glucocerebrosidase gene with high susceptibility to Parkinson s disease among Chinese . Chin J Physiol. 2012 ; 55 : 398-404 .
73. Kumar KR, Ramirez A, G o bel A, Kresojevi ? N, Svetel M, Lohmann K, et al . Glucocerebrosidase mutations in a Serbian Parkinson s disease population . Eur J Neurol. 2013 ; 20 : 402-5 .
74. Wang Y, Liu L, Xiong J, Zhang X, Chen Z, Yu L, et al. Glucocerebrosidase L444P mutation confers genetic risk for Parkinson s disease in central China. Behav Brain Funct. 2012; 8: 57
75. R inco n M D, M onroy Jaramillo N , S ua r ez Marti n ez A , Y escas Go m ez P , Boll Woehrlen M , L o pez L o pez M , et al . Th e L444P GBA mutation is associated with early-onset Parkinson s disease in Mexican Mestizos . Clin Genet. 2013; 84: 386-7
76. Lees AJ, Hardy J, Revesz T. Parkinson s disease. Lancet. 2009: 373; 2055-66 .
77. S avica R , R occa W A, A hlskog J E. W hen does Parkinson disease start? Arch Neurol. 2010; 67: 798-801
78. S chapira A H, T olosa E . M olecular and clinical prodrome of Parkinson disease: implications for treatment . Nat Rev Neurol. 2010 ; 6 : 309-17 .
79. Braak H, Del Tredici K, R u b U, de Vos RA, Jansen Steur EN, Break E. Staging of brain pathology related to sporadic Parkinson s disease . Neurobiol Aging. 2003; 24: 197
80. McNeill A, Wu RM, Tzen KY, Aguiar PC, Arbelo JM, Barone P, et al. Dopaminergic neuronal imaging in genetic Parkinson s disease: insights into pathogenesis. PLoS One. 2013; 8: e69190
81. Kono S, Ouchi Y, Terada T, Ida H, Suzuki M, Miyajima H. Functional brain imaging in glucocerebrosidase mutation carriers with and without parkinsonism. Mov Disord. 2010; 25: 1823-9
82. Goker-Alpan O, Masdeu JC, Kohn PD, Ianni A, Lopez G, Groden C, et al . Th e neurobiology of glucocerebrosidase-associated parkinsonism: a positron emission tomography study of dopamine synthesis and regional cerebral blood fl ow . Brain. 2012 ; 135 : 2440-8 .
83. Hagenah J, K o nig IR, Sperner J, Wessel L, Seidel G, Condefer K, et al. Life-long increase of substantia nigra hyperechogenicity in transcranial sonography . Neuroimage. 2010; 51: 28-32
84. Berg D, Godau J, Walter U. Transcranial sonography in movement disorders. Lancet Neurol. 2008; 7: 1044-55
85. B o t tcher T , R olfs A , M eyer B , G rossmann A , B erg D , K ropp P . C linical, genetic, and brain sonographic features related to Parkinson s disease in Gaucher disease . J Neurol. 2013 Jun 29 . [Epub ahead of print].
86. Schmid SP, Schleicher ED, Cegan A, Deuschle C, Baur S, Hauser AK, et al . Cerebrospinal fl uid fatty acids in glucocerebrosidase-associated Parkinson s disease. Mov Discord. 2012; 27: 288-92
87. Machaczka M, Arce MP, Rucinska M, Yoshitake T, Kehr J, Jurczak W, et al . A twelve-year follow-up study on a case of early-onset parkinsonism preceding clinical manifestation of Gaucher disease . JIMD Rep. 2012 ; 3 : 53-7
88. S idransky E , L opez G . Th e link between the GBA gene and parkinsonism. Lancet Neurol. 2012; 11: 986-98
89. Mazzulli JR, Xu YH, Sun Y, Knight AL, McLean PJ, Caldwell GA, et al. Gaucher disease glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell. 2011; 146: 37-52
90. Cullen V, Sardi SP, Ng J, Xu YH, Sun Y, Tomlinson JJ, et al. Acid -glucosidase mutants linked to Gaucher disease, Parkinson disease, and Lewy body dementia alter -synuclein processing . Ann Neurol. 2011 ; 69 : 940-53 .
91. Manning-Bo ? AB, Sch u le B, Langston JW. Alpha-synuclein- glucocerebrosidase interactions in pharmacological Gaucher models: a biological link between Gaucher disease and parkinsonism . Neurotoxicology. 2009; 30: 1127-32
92. Cleeter MW, Chau KY, Gluck C, Mehta A, Hughes DA, Duchen M, et al . Glucocerebrosidase inhibition causes mitochondrial dysfunction and free radical damage . Neurochem Int. 2013 ; 62 : 1-7 .
93. Xu YH, Sun Y, Ran H, Quinn B, Witte D, Grabowski GA. Accumulation and distribution of SNCA and ubiquitin in the CNS of Gaucher disease mouse models. Mol Genet Metab. 2011; 102: 436-47
94. Gegg ME, Burke D, Heales SJ, Cooper JM, Hardy J, Wood NW, et al. Glucocerebrosidase defi ciency in substantia nigra of parkinson disease brains . Ann Neurol. 2012; 72: 455-63
95. Osellame LD, Rahim AA, Hargreaves IP, Gegg ME, Richard-Londt A, Brandner S , et al . Mitochondria and quality control defects in a mouse model of Gaucher Disease-links to Parkinson s disease . Cell Metab. 2013 ; 17 : 941-53 .
96. Dermentzaki G, Dimitriou E, Xilouri M, Michelakakis H, Stefanis L. Loss of -glucocerebrosidase activity does not aff ect alpha-synuclein levels or lysosomal function in neuronal cells . PLoS One. 2013 ; 8 : e60674 .
97. Yap TL, Velayati A, Sidransky E, Lee JC. Membrane-bound SNCA interacts with glucocerebrosidase and inhibits enzyme activity . Mol Genet Metab. 2013; 108: 56-64
98. Yap TL, Gruschus JM, Velayati A, Westbroek W, Goldin E, Moaven N, et al . Alpha-synuclein interacts with glucocerebrosidase providing a molecular link between Parkinson and Gaucher diseases . J Biol Chem. 2011 ; 286 : 28080-8 .
99. S chapira A H, G egg M E. G lucocerebrosidase in the pathogenesis and treatment of Parkinson disease . Proc Natl Acad Sci U S A. 2013 ; 110 : 3214-15 .
100. D e Duve C , W attiaux R . F unctions of lysosomes. 1 966; 2 8: 4 35-9 2
101. Garc i a-Arencibia M, Hochfeld WE, Toh PP, Rubinsztein DC. Autophagy-A guardian against neurodegeneration . Semin Cell Dev Biol. 2010 ; 21 : 691-8 .
102. Wong E, Cuervo AM. Autophagy gone awry in neurodegenerative diseases. Nat Neurosci. 2010; 13: 805-11
103. Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D. Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy . Science. 2004; 305: 1292-5 (Pubitemid 39129234)
104. Alvarez-Erviti L, Rodriguez-Oroz MC, Cooper JM, Caballero C, Ferrer I, Obeso JA , et al . Chaperone-mediated autophagy markers in Parkinson disease brains . Arch Neurol. 2010; 67: 1464-72
105. Dehay B, Bov e J, Rodriguez-Muela N, Perier C, Recasens A, Boya P, et al . Pathogenic lysosomal depletion in Parkinson s disease. J Neurosci. 2010 ; 30 : 12535-44 .
106. Tong Y, Yamaguchi H, Giaime E, Boyle S, Kopan R, Kelleher RJ 3rd, et al . Loss of leonine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of alpha-synuclein, and apoptotic cell death in aged mice . Proc Natl Acad Sci U S A. 2010 ; 9879-84 .
107. : Orenstein SJ, Kuok SH, Tassel I, Arias E, Koga H, Fernandez-Carasa I, et al . Interplay of LRRK2 with chaperone-mediated autophagy . Nat Neurosci. 2013; 16: 394-406
108. Mak SK, McCormack AL, Manning-Bog AB, Cuervo AM, Di Monte DA . Lysosomal degradation of alpha-synuclein in vivo . J Biol Chem. 2010 ; 285 : 13621-9 .
109. Cuero AM. Consequences of the selective blockage of chaperone-mediated autophagy . Proc Natal Acad Sci U S A. 2006; 103: 5805-10
110. Kiffi n R , K aushik S , Z eng M , B andyopadhyay U , Z hang C , M assey A C, et al . Altered dynamics of the lysosomal receptor for chaperonemediated autophagy with age . J Cell Sci. 2007; 120: 782-91 (Pubitemid 46523480)
111. Spencer B, Pokar R, Trejo M, Rockenstein E, Patrick C, Gindi R, et al. Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinsons and Lewy body diseases. J Neurosci. 2009; 29: 13578-88
112. McNaught KS, Belizaire R, Isacson O, Jenner P, Olanow CW. Altered proteasomal function in sporadic Parkinson s disease . Exp Neurol. 2003 ; 179 : 38-46 . (Pubitemid 36062617)
113. Furukawa Y, Vigouroux S, Wong H, Guttman M, Rajput AH, Ang L, et al . Brain proteasomal function in sporadic Parkinson s disease and related disorders. Ann Neurol. 2002; 51: 779-82 (Pubitemid 34568860)
114. Beal F, Lang A. Th e proteasomal inhibition model of Parkinson s disease: Boon or bust? Ann Neurol. 2006; 60: 158-61 (Pubitemid 44182390)
115. R on I , H orowitz M . E R retention and degradation as the molecular basis underlying Gaucher disease heterogeneity . Hum Mol Genet. 2005 ; 14 : 2387-98 . (Pubitemid 41418000)
116. Wang M, Ye R, Barron E, Baumeister P, Mao C, Luo S, et al. Essential role of the unfolded protein response regulator GRP78/BiP in protection from neuronal apoptosis . Cell Death Diff er. 2010; 17: 488-98
117. Ron I, Rapaport D, Horowitz M. Interaction between parkin and mutant glucocerebrosidase variants: a possible link between Parkinson disease and Gaucher disease. Hum Mol Genet. 2010; 19: 3771-81
118. I mai Y , S oda M , T akahashi R . P arkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity . J Biol Chem. 2000 ; 275 : 35661-4 .
119. McNeill A, Healy DG, Schapira AH, Taanman JW. Glucosylceramidase degradation in fi broblasts carrying bi-allelic Parkin mutations . Mol Genet Metab. 2013; 109: 402-3
120. Schapira AH. Mitochondria in the aetiology and pathogenesis of Parkinson s disease. Lancet Neurol. 2008; 7: 97-109 (Pubitemid 350251942)
121. Schapira AH, Gegg M. Mitochondrial contribution to Parkinson s disease pathogenesis. Parkinsons Dis. 2011; 159160
122. Poole AC, Th omas RE, Andrews LA, McBride HM, Whitworth AJ, Pallanck LJ . Th e PINK1/Parkin pathway regulates mitochondrial morphology . Proc Natl Acad Sci U S A. 2008; 105: 1638-43 (Pubitemid 351346567)
123. Narendra D, Tanaka A, Suen DF, Youle RJ. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy . J Cell Biol. 2008 ; 183 : 795-803 .
124. K im Y , P ark J , K im S , S ong S , K won S K, L ee S H, e t a l. P INK1 controls mitochondrial localization of Parkin through direct phosphorylation . Biochem Biophys Res Commun. 2008; 377: 975-80
125. Bras J, Singleton A, Cookson MR, Hardy J. Emerging pathways in genetic Parkinson s disease: potential role of ceramide metabolism in Lewy body disease. FEBS J. 2008; 275: 5767-73
126. Jo E, McLaurin J, Yip CM, St George-Hyssop P, Fraser PE. Alphasynuclein membrane interactions and lipid specifi city . J Biol Chem. 2000 ; 275 : 34328-34 .
127. Piccinini M, Scandroglio F, Prioni S, Buccinn a B, Loberto N, Aureli M, et al . Deregulated sphingolipid metabolism and membrane organization in neurodegenerative disorders. Mol Neurobiol. 2010; 41: 314-40
128. Velayati A, Yu WH, Sidransky E. Th e role of glucocerebrosidase mutations in Parkinson disease and Lewy body disorders . Curr Neurol Neurosci Rep. 2010; 10: 190-8
129. Sardi SP, Clarke J, Viel C, Chan M, Tamsett TJ, Treleaven CM, et al. Augmenting CNS glucocerebrosidase activity as a therapeutic strategy for parkinsonism and other gaucher-related synucleinopathies . Proc Natl Acad Sci U S A. 2013 ; 110 : 3537-42 .
130. Korolchuk VI, Mansilla A, Menzies FM, Rubinsztein DC. Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates. Mol Cell. 2009; 33: 517-27
131. Settembre C, Fraldi A, Rubinsztein DC, Ballabio A. Lysosomal storage diseases as disorders of autophagy . Autophagy. 2008b; 4: 113-14
132. Dehay B, Martinez-Vicente M, Caldwell GA, Caldwell KA, Yue Z, Cookson MR , et al . Lysosomal impairment in Parkinson s disease. Mov Disord. 2013; 28: 725-32.