Gaucher disease and the synucleinopathies: refining the relationship

Orphanet Journal of Rare Diseases

Francis YM Choy²  Tessa N Campbell¹ 

[1] TNC Scientific Consulting, Calgary, AB, Canada;Department of Biology, University of Victoria, PO Box 3020, Station CSC, Victoria, BC, V8W 3N5, Canada

关键词: protein misfolding;    neurodegeneration with brain iron accumulation;    multiple system atrophy;    dementia with Lewy bodies;    Parkinson's disease;    synucleinopathies;    lysosomal storage disease;    GBA mutations;    glucocerebrosidase;    Gaucher disease;   

Others  :  864453
DOI  :  10.1186/1750-1172-7-12

 received in 2011-08-23, accepted in 2012-01-31,  发布年份 2012

【 摘 要 】

Gaucher disease (OMIM 230800, 230900, 231000), the most common lysosomal storage disorder, is due to a deficiency in the enzyme glucocerebrosidase. Gaucher patients display a wide spectrum of clinical presentation, with hepatosplenomegaly, haematological changes, and orthopaedic complications being the predominant symptoms. Gaucher disease is classified into three broad phenotypes based upon the presence or absence of neurological involvement: Type 1 (non-neuronopathic), Type 2 (acute neuronopathic), and Type 3 (subacute neuronopathic). Nearly 300 mutations have been identified in Gaucher patients, with the majority being missense mutations. Though studies of genotype-to-phenotype correlations have revealed significant heterogeneity, some consistent patterns have emerged to inform prognostic and therapeutic decisions. Recent research has highlighted a potential role for Gaucher disease in other comorbidities such as cancer and Parkinson's Disease. In this review, we will examine the potential relationship between Gaucher disease and the synucleinopathies, a group of neurodegenerative disorders characterized by the development of intracellular aggregates of α-synuclein. Possible mechanisms of interaction will be discussed.

【 授权许可】

   
2012 Campbell and Choy; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Harmanci O, Bayraktar Y: Gaucher disease: new developments in treatment and etiology. World J Gastroenterol 2008, 14:3968-3973.
• [2]Choy FYM, Campbell TN: Gaucher disease and cancer: concept and controversy. Int J Cell Biol 2011, 2011:Article ID 150450, 6 pages.
• [3]Beutler E, Grabowski GA: Gaucher disease. In The Metabolic and Molecular Bases of Inherited Disease. Edited by Scriver CR, Beaudet AL, Sly WS. New York: McGraw-Hill; 2001:3635-3668.
• [4]Choy FY, Zhang W, Shi HP, Zay A, Campbell T, Tang N, Ferreira P: Gaucher disease among Chinese patients: review on genotype/phenotype correlation from 29 patients and identification of novel and rare alleles. Blood Cell Mol Dis 2007, 38:287-293.
• [5]Hruska KS, LaMarca ME, Scott CR, Sidransky E: Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA). Human Mutation 2008, 29:567-583.
• [6]Beutler E, Gelbart T, Scott CR: Hematologically important mutations: Gaucher disease. Blood Cell Mol Dis 2005, 35:355-364.
• [7]de Fost M, Aerts JM, Hollak CE: Gaucher disease: from fundamental research to effective therapeutic interventions. Neth J Med 2003, 61:3-8.
• [8]Elstein D, Zimran A: Review of the safety and efficacy of imiglucerase treatment of Gaucher disease. J Biologics 2009, 3:407-417.
• [9]Aerts JM, Yasothan M, Kirkpatrick P: Velglucerase alfa. Nat Rev Drug Discovery 2010, 9:837-838.
• [10]Lukina E, Watman N, Arreguin EA, Dragosky M, Iastrebner M, Rosenbaum H, Phillips M, Pastores GM, Kamath RS, Rosenthal DI, Kaper M, Singh T, Puga AC, Peterschmitt MJ: Improvement in hematological, visceral, and skeletal manifestations of Gaucher disease type 1 with oral eliglustat tartrate (Genz- 112638) treatment: 2-year results of a phase 2 study. Blood 2010, 116:4095-4098.
• [11]Cox TM: Gaucher disease: clinical profile and therapeutic developments. J Biologics 2010, 4:299-313.
• [12]Galvin JE, Lee V, Trojanowski JQ: Synucleinopathies: clinical and pathological implications. Arch Neurol 2001, 58:186-190.
• [13]Maroteaux L, Campanelli JT, Scheller RH: Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci 1988, 8:2804-2815.
• [14]Clayton DF, George JM: Synucleins in synaptic plasticity and neurodegenerative disorders. J Neurosci Res 1999, 58:120-129.
• [15]Spillantini MG, Divane A, Goedert M: Assignment of human alpha-synuclein (SNCA) and beta-synuclein (SNCB) genes to chromosomes 4q21 and 5q35. Genomics 1995, 27:379-381.
• [16]de Rijk MC, Launer LJ, Berger K, Breteler MM, Dartigues JF, Baldereschi M, Fratiglioni L, Lobo A, Martinez-Lage J, Trenkwalder C, Hofman A: Prevalence of Parkinson's disease in Europe: a collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology 2000, 54(11 suppl 5):S21-S23.
• [17]Bekris LM, Mata IF, Zabetian CP: The genetics of Parkinson disease. J Geriatr Psychiatry Neurol 2010, 23(4):228-242.
• [18]Sellbach AN, Boyle RS, Silburn PA, Mellick GD: Parkinson's disease and family history. Parkinsonism Relat Disord 2006, 12(7):399-409.
• [19]Polymeropoulos MH, Higgins JJ, Golbe LI, Johnson WG, Ide SE, Di Iorio G, Sanges G, Stenroos ES, Pho LT, Schaffer AA, Lazzarini AM, Nussbaum RL, Duvoisin RC: Mapping of a gene for Parkinson's disease to chromosome 4q21-q23. Science 1996, 274(5290):1197-1199.
• [20]Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL: Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 1997, 276(5321):2045-2047.
• [21]Lesage S, Brice A: Parkinson's disease: from monogenic forms to genetic susceptibility factors. Hum Mol Genet 2009, 18(R1):R48-R59.
• [22]Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, Bar-Shira A, Berg D, Bras J, Brice A, Chen CM, Clark LN, Condroyer C, De Marco EV, Dürr A, Eblan MJ, Fahn S, Farrer MJ, Fung HC, Gan-Or Z, Gasser T, Gershoni-Baruch R, Giladi N, Griffith A, Gurevich T, Januario C, Kropp P, Lang AE, Lee-Chen GJ, Lesage S, Marder K, Mata IF, Mirelman A, Mitsui J, Mizuta I, Nicoletti G, Oliveira C, Ottman R, Orr-Urtreger A, Pereira LV, Quattrone A, Rogaeva E, Rolfs A, Rosenbaum H, Rozenberg R, Samii A, Samaddar T, Schulte C, Sharma M, Singleton A, Spitz M, Tan EK, Tayebi N, Toda T, Troiano AR, Tsuji S, Wittstock M, Wolfsberg TG, Wu YR, Zabetian CP, Zhao Y, Ziegler SG: Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N Engl J Med 2009, 361(17):1651-1661.
• [23]Goker-Alpan O, Schiffmann R, LaMarca ME, Nussbaum RL, McInerney-Leo A, Sidransky E: Parkinsonism among Gaucher disease carriers. J Med Genet 2004, 41:937-940.
• [24]Halperin A, Elstein D, Zimran A: Increased incidence of Parkinson disease among relatives of patients with Gaucher disease. Blood Cell Mol Dis 2006, 6:426-428.
• [25]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, 351:1972-1977.
• [26]Sato C, Morgan A, Lang AE, Salehi-Rad S, Kawarai T, Meng Y, Ray PN, Farrer LA, St George-Hyslop P, Rogaeva E: Analysis of the glucocerebrosidase gene in Parkinson's disease. Mov Disord 2005, 20:367-370.
• [27]Toft M, Pielsticker L, Ross OA, Aasly JO, Farrer MJ: Glucocerebrosidase gene mutations and Parkinson disease in the Norwegian population. Neurology 2006, 66:415-417.
• [28]Tan EK, Tong J, Fook-Chong S, Yih Y, Wong MC, Pavanni R, Zhao Y: Glucocerebrosidase mutations and risk of Parkinson disease in Chinese patients. Arch Neurol 2007, 64:1056-1058.
• [29]Mata IF, Samii A, Schneer SH, Roberts JW, Griffith A, Leis BC, Schellenberg GD, Sidransky E, Bird TD, Leverenz JB, Tsuang D, Zabetian CP: Glucocerebrosidase gene mutations: a risk factor for Lewy body disorders. Arch Neurol 2008, 65:379-382.
• [30]Spitz M, Rozenberg R, Pereira Lda V, Reis Barbosa E: Association between Parkinson's disease and glucocerebrosidase mutations in Brazil. Parkinsonism Relat Disord 2008, 14:58-62.
• [31]Leverenz JB, Lopez OL, Dekosky ST: The expanding role of genetics in the lewy body diseases: the glucocerebrosidase gene. Arch Neurol 2009, 66(5):555-556.
• [32]Mitsui J, Mizuta I, Toyoda A, Ashida R, Takahashi Y, Goto J, Fukuda Y, Date H, Iwata A, Yamamoto M, Hattori N, Murata M, Toda T, Tsuji S: Mutations for Gaucher disease confer high susceptibility to Parkinson disease. Arch Neurol 2009, 66:571-576.
• [33]Neumann J, Bras J, Deas E, O'Sullivan SS, Parkkinen L, Lachmann RH, Li A, Holton J, Guerreiro R, Paudel R, Segarane B, Singleton A, Lees A, Hardy J, Houlden H, Revesz T, Wood NW: Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease. Brain 2009, 132(Pt 7):1783-1794.
• [34]Lesage S, Anheim M, Condroyer C, Pollak P, Durif F, Dupuits C, Viallet F, Lohmann E, Corvol JC, Honoré A, Rivaud S, Vidailhet M, Dürr A, Brice A: Large-scale screening of the Gaucher's disease-related glucocerebrosidase gene in Europeans with Parkinson's disease. Hum Mol Genet 2011, 20(1):202-10.
• [35]McKeith I, Mintzer J, Aarsland D, Burn D, Chiu H, Cohen-Mansfield J, Dickson D, Dubois B, Duda JE, Feldman H, Gauthier S, Halliday G, Lawlor B, Lippa C, Lopez OL, Carlos Machado J, O'Brien J, Playfer J, Reid W: Dementia with Lewy bodies. Lancet Neurol 2004, 3:19-28.
• [36]Neef D, Walling AD: Dementia with Lewy bodies: an emerging disease. Am Fam Physician 2006, 73:1223-1230.
• [37]McKeith IG, Galasko D, Kosaka K, Perry EK, Dickson DW, Hansen LA, Salmon DP, Lowe J, Mirra SS, Byrne EJ, Lennox G, Quinn NP, Edwardson JA, Ince PG, Bergeron C, Burns A, Miller BL, Lovestone S, Collerton D, Jansen EN, Ballard C, de Vos RA, Wilcock GK, Jellinger KA, Perry RH: Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 1996, 47:1113-1124.
• [38]Boeve BF, Silber MH, Ferman TJ, Lucas JA, Parisi JE: Association of REM sleep behavior disorder and neurodegenerative disease may reflect an underlying synucleinopathy. Mov Disord 2001, 16(4):622-30.
• [39]Mollenhauer B, Forstl H, Deuschl G, Storch A, Oertel W, Trenkwalder C: Lewy body and parkinsonian dementia: common, but often misdiagnosed conditions. Dtsch Arztebl Int 2010, 107(39):684-91.
• [40]Velayati A, Yu WH, Sidransky E: The role of glucocerebrosidase mutations in Parkinson disease and Lewy body disorders. Curr Neurol Neurosci Rep 2010, 10:190-198.
• [41]Goker-Alpan O, Giasson BI, Eblan MJ, Nguyen J, Hurtig HI, Lee VM, Trojanowski JQ, Sidransky E: Glucocerebrosidase mutations are an important risk factor for Lewy body disorders. Neurology 2006, 67:908-910.
• [42]Farrer MJ, Williams LN, Algom AA, Kachergus J, Hulihan MM, Ross OA, Rajput A, Papapetropoulos S, Mash DC, Dickson DW: Glucosidase-beta variations and Lewy body disorders. Parkinsonism Relat Disord 2009, 15:414-416.
• [43]Clark LN, Kartsaklis LA, Wolf Gilbert R, Dorado B, Ross BM, Kisselev S, Verbitsky M, Mejia-Santana H, Cote LJ, Andrews H, Vonsattel JP, Fahn S, Mayeux R, Honig LS, Marder K: Association of glucocerebrosidase mutations with dementia with lewy bodies. Arch Neurol 2009, 66:578-583.
• [44]Parnetti L, Balducci C, Pierguidi L, De Carlo C, Peducci M, D'Amore C, Padiglioni C, Mastrocola S, Persichetti E, Paciotti S, Bellomo G, Tambasco N, Rossi A, Beccari T, Calabresi P: Cerebrospinal fluid β-glucocerebrosidase activity is reduced in Dementia with Lewy Bodies. Neurobiol Dis 2009, 34:484-486.
• [45]Balducci C, Pierguidi L, Persichetti E, Parnetti L, Sbaragli M, Tassi C, Orlacchio A. Calabresi P, Beccari T, Rossi A: Lysosomal hydrolases in cerebrospinal fluid from subjects with Parkinson's disease. Mov Disord 2007, 22:1481-1484.
• [46]Stemberger S, Scholz SW, Singleton AB, Wenning GK: Genetic players in multiple system atrophy: unfolding the nature of the beast. Neurobiol Aging 2011, 32(10):1924.e5-14.
• [47]Watanabe H, Saito Y, Terao S, Ando T, Kachi T, Mukai E, Aiba I, Abe Y, Tamakoshi A, Doyu M, Hirayama M, Sobue G: Progression and prognosis in multiple system atrophy: an analysis of 230 Japanese patients. Brain 2002, 125:1070-1083.
• [48]Schrag A, Wenning GK, Quinn N, Ben- Shlomo Y: Survival in multiple system atrophy. Mov Disord 2008, 23:294-296.
• [49]Shimohata T, Ozawa T, Nakayama H, Tomita M, Shinoda H, Nishizawa M: Frequency of nocturnal sudden death in patients with multiple system atrophy. J Neurol 2008, 255:1483-1485.
• [50]Flabeau O, Meissner WG, Tison F: Multiple system atrophy: current and future approaches to management. Ther Adv Neurol Disord 2010, 3(4):249-263.
• [51]Wenning GK, Stefanova N, Jellinger KA, Poewe W, Schlossmacher MG: Multiple system atrophy: a primary oligodendrogliopathy. Ann Neurol 2008, 64:239-246.
• [52]Lantos PL: The definition of multiple system atrophy: a review of recent developments. J Neuropathol Exp Neurol 1998, 57:1099-1111.
• [53]Spillantini MG, Crowther RA, Jakes R, Cairns NJ, Lantos PL, Goedert M: Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson's disease and dementia with Lewy bodies. Neurosci Lett 1998, 251:205-208.
• [54]Wakabayashi K, Yoshimoto M, Tsuji S, Takahashi H: Alphasynuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci Lett 1998, 249:180-182.
• [55]Brown RC, Lockwood AH, Sonawane BR: Neurodegenerative diseases: an overview of environmental risk factors. Environ Health Perspect 2005, 113:1250-1256.
• [56]Galvin JE, Giasson B, Hurtig HI, Lee VM, Trojanowski JQ: Neurodegeneration with brain iron accumulation, type 1 is characterized by alpha-, beta-, and gamma-synuclein neuropathology. Am J Pathol 2000, 157(2):361-368.
• [57]Paisan-Ruiz C, Li A, Schneider SA, Holton JL, Johnson R, Kidd D, Chataway J, Bhatia KP, Lees AJ, Hardy J, Revesz T, Houlden H: Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations. Neurobiol Aging 2010, in press.
• [58]Hayflick SJ, Westaway SK, Levinson B, Zhou B, Johnson MA, Ching KH, Gitschier J: Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome. N Engl J Med 2003, 348:33-40.
• [59]Gregory A, Polster BJ, Hayflick SJ: Clinical and genetic delineation of neurodegeneration with brain iron accumulation. J Med Genet 2009, 46(2):73-80.
• [60]Zhou B, Westaway SK, Levinson B, Johnson MA, Gitschier J, Hayflick SJ: A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat Genet 2001, 28:345-349.
• [61]Harris ZL, Takahashi Y, Miyajima H, Serizawa M, MacGillivray RT, Gitlin JD: Aceruloplasminemia: molecular characterization of this disorder of iron metabolism. Proc Natl Acad Sci USA 1995, 92:2539-2543.
• [62]Curtis AR, Fey C, Morris CM, Bindoff LA, Ince PG, Chinnery PF, Coulthard A, Jackson MJ, Jackson AP, McHale DP, Hay D, Barker WA, Markham AF, Bates D, Curtis A, Burn J: Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nat Genet 2001, 28:350-354.
• [63]Gregory A, Hayflick SJ: Genetics of neurodegeneration with brain iron accumulation. Curr Neurol Neurosci Rep 2011, 11:254-261.
• [64]Segarane B, Li A, Paudel R, Scholz S, Neumann J, Lees A, Revesz T, Hardy J, Mathias CJ, Wood NW, Holton J, Houlden H: Glucocerebrosidase mutations in 108 neuropathologically confirmed cases of multiple system atrophy. Neurology 2009, 72:1185-1186.
• [65]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(3):459-60.
• [66]Goldin E: Gaucher disease and parkinsonism, a molecular link theory. Mol Genet Metab 2010, 101:307-310.
• [67]Depaolo J, Goker-Alpan O, Samaddar T, Lopez G, Sidransky E: The association between mutations in the lysosomal protein glucocerebrosidase and parkinsonism. Mov Disord 2009, 24(11):1571-1578.
• [68]Cullen V, Sardi SP, Ng J, Xu YH, Sun Y, Tomlinson JJ, Kolodzeij P, Kahn I, Saftiq P, Woulfe J, Rochet JC, Glicksman MA, Cheng SH, Grabowski GA, Shihabuddin LS, Schlossmacher MG: Acid β-glucosidase mutants linked to Gaucher disease, Parkinson disease, and Lewy body dementia alter α-synuclein processing. Ann Neurol 2011, 69(6):940-953.
• [69]Jo E, McLaurin J, Yip CM, St George-Hyslop P, Fraser PE: Alpha-Synuclein membrane interactions and lipid specificity. J Biol Chem 2000, 275(44):34328-34334.
• [70]Velayati A, Yu WH, Sidransky E: The role of glucocerebrosidase mutations in Parkinson disease and Lewy body disorders. Curr Neurol Neurosci Rep 2010, 10(3):190-198.
• [71]Pelled D, Trajkovic-Bodennec S, Lloyd-Evans E, Sidransky E, Schiffmann R, Futerman AH: Enhanced calcium release in the acute neuronopathic form of Gaucher disease. Neurobiol Dis 2005, 18:83-88.
• [72]Mazzulli JR, Xu YH, Sun Y, Knight AL, McLean PJ, Caldwell GA, Sidransky E, Grabowski GA, Krainc D: Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 2011, 146(1):37-52.
• [73]Olanow CW, Prusiner SB: Is Parkinson's disease a prion disorder? Proc Natl Acad Sci USA 2009, 106:12571-12572.
• [74]Westbroek W, Gustafson AM, Sidransky E: Exploring the link between glucocerebrosidase mutations and parkinsonism. Trends Mol Med 2011, in press.
• [75]Sardi SP, Clarke J, Kinnecom C, Tamsett TJ, Li L, Stanek LM, Passini MA, Grabowski GA, Schlossmacher MG, Sidman RL, Cheng SH, Shihabuddin LS: CNS expression of glucocerebrosidase corrects alpha-synuclein pathology andmemory in a mouse model of Gaucher-related synucleinopathy. Proc Natl Acad Sci USA 2011, 108(29):12101-12106.
• [76]Choi JH, Stubblefield B, Cookson MR, Goldin E, Velayati A, Tayebi N, Sidransky E: Aggregation of α-synuclein in brain samples from subjects with glucocerebrosidase mutations. Mol Genet Metab 2011, 104(1-2):185-188.
• [77]Hruska KS, Goker-Alpan O, Sidransky E: Gaucher disease and the synucleinopathies. Biomed Biotechnol 2006, 2006:Article ID 78549, Pages 1-6.