BRAIN and NERVE－神経研究の進歩72巻2号

2020年02月発行

特集 αシヌクレイノパチーの新たな展開

αシヌクレインと家族性パーキンソン病—未来への展望

著者： 西岡健弥¹ 服部信孝¹

所属機関： ¹順天堂大学医学部附属順天堂医院脳神経内科

ページ範囲：P.119 - P.129

文献概要

この20年の間に家族性パーキンソン病の原因遺伝子や疾患感受性遺伝子の同定が相次いでいる。PARK分類は23まで増えており，さらに関連遺伝子の報告は続いている。本総説では，SNCA遺伝子変異の同定から，その歴史について述べ，その後，近年同定された遺伝子の中で，レヴィ小体の形成に関与する遺伝子群について解説を行う。同定された背景，その臨床像や分子病態，機能について，自験例も踏まえながら解説を行う。

参考文献

1)Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, et al: Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 276: 2045-2047, 1997

2)Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, et al: Alpha-synuclein in Lewy bodies. Nature 388: 839-840, 1997

3)Kim WS, Kågedal K, Halliday GM: Alpha-synuclein biology in Lewy body diseases. Alzheimers Res Ther 6: 73, 2014

4)Nishioka K, Hayashi S, Farrer MJ, Singleton AB, Yoshino H, et al: Clinical heterogeneity of alpha-synuclein gene duplication in Parkinson's disease. Ann Neurol 59: 298-309, 2006

5)Nishioka K, Ross OA, Ishii K, Kachergus JM, Ishiwata K, et al: Expanding the clinical phenotype of SNCA duplication carriers. Mov Disord 24: 1811-1819, 2009

6)Miller DW, Hague SM, Clarimon J, Baptista M, Gwinn-Hardy K, et al: Alpha-synuclein in blood and brain from familial Parkinson disease with SNCA locus triplication. Neurology 62: 1835-1838, 2004

7)Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, et al: alpha-Synuclein locus triplication causes Parkinson's disease. Science 302: 841, 2003

8)Krüger R, Kuhn W, Müller T, Woitalla D, Graeber M, et al: Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nat Genet 18: 106-108, 1998

9)Zarranz JJ, Alegre J, Gomez-Esteban JC, Lezcano E, Ros R, et al: The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 55: 164-173, 2004

10)Lesage S, Anheim M, Letournel F, Bousset L, Honoré A, et al: G51D alpha-synuclein mutation causes a novel parkinsonian-pyramidal syndrome. Ann Neurol 73: 459-471, 2013

11)Proukakis C, Dudzik CG, Brier T, MacKay DS, Cooper JM, et al: A novel alpha-synuclein missense mutation in Parkinson disease. Neurology 80: 1062-1064, 2013

12)Pasanen P, Myllykangas L, Siitonen M, Raunio A, Kaakkola S, et al: Novel alpha-synuclein mutation A53E associated with atypical multiple system atrophy and Parkinson's disease-type pathology. Neurobiol Aging 35: e1-e5, 2014［doi: 10.1016/j.neurobiolaging.2014.03.024］

13)Yoshino H, Hirano M, Stoessl AJ, Imamichi Y, Ikeda A, et al: Homozygous alpha-synuclein p.A53V in familial Parkinson's disease. Neurobiol Aging 57: e7-e12, 2017［doi: 10.1016/j.neurobiolaging.2017.05.022］

14)Book A, Guella I, Candido T, Brice A, Hattori N, et al: A Meta-Analysis of alpha-Synuclein Multiplication in Familial Parkinsonism. Front Neurol 9: 1021, 2018［doi: 10.3389/fneur.2018.01021］

15)Feany MB, Bender WW: A Drosophila model of Parkinson's disease. Nature 404: 394-398, 2000

16)Funayama M, Hasegawa K, Kowa H, Saito M, Tsuji S, et al: A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2-q13.1. Ann Neurol 51: 296-301, 2002

17)Paisán-Ruíz C, Jain S, Evans EW, Gilks WP, Simón J, et al: Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 44: 595-600, 2004

18)Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, et al: Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44: 601-607, 2004

19)Healy DG, Falchi M, O'Sullivan SS, Bonifati V, Durr A, et al: Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurol 7: 583-590, 2008

20)Schneider SA, Alcalay RN: Neuropathology of genetic synucleinopathies with parkinsonism: Review of the literature. Mov Disord 32: 1504-1523, 2017

21)Takanashi M, Funayama M, Matsuura E, Yoshino H, Li Y, et al: Isolated nigral degeneration without pathological protein aggregation in autopsied brains with LRRK2 p.R1441H homozygous and heterozygous mutations. Acta Neuropathol Commun 6: 105, 2018［doi: 10.1186/s40478-018-0617-y］

22)Hasegawa K, Stoessl AJ, Yokoyama T, Kowa H, Wszolek ZK, et al: Familial parkinsonism: study of original Sagamihara PARK8 (I2020T) kindred with variable clinicopathologic outcomes. Parkinsonism Relat Disord 15: 300-306, 2009

23)Satake W, Nakabayashi Y, Mizuta I, Hirota Y, Ito C, et al: Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease. Nat Genet 41: 1303-1307, 2009

24)Nalls MA, Pankratz N, Lill CM, Do CB, Hernandez DG, et al: Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nat Genet 46: 989-993, 2014

25)Pankratz N, Beecham GW, DeStefano AL, Dawson TM, Doheny KF, et al: Meta-analysis of Parkinson's disease: identification of a novel locus, RIT2. Ann Neurol 71: 370-384, 2012

26)Chang D, Nalls MA, Hallgrímsdóttir IB, Hunkapiller J, van der Brug M, et al: A meta-analysis of genome-wide association studies identifies 17 new Parkinson's disease risk loci. Nat Genet 49: 1511-1516, 2017

27)Puschmann A, Fiesel FC, Caulfield TR, Hudec R, Ando M, et al: Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism. Brain 140: 98-117, 2017

28)Pickrell AM, Youle RJ: The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson's disease. Neuron 85: 257-273, 2015

29)Wijemanne S, Jankovic J: Dopa-responsive dystonia--clinical and genetic heterogeneity. Nat Rev Neurol 11: 414-424, 2015

30)Yoshino H, Nishioka K, Li Y, Oji Y, Oyama G, et al: GCH1 mutations in dopa-responsive dystonia and Parkinson's disease. J Neurol 265: 1860-1870, 2018

31)Mencacci NE, Isaias IU, Reich MM, Ganos C, Plagnol V, et al: Parkinson's disease in GTP cyclohydrolase 1 mutation carriers. Brain 137: 2480-2492, 2014

32)Segawa M, Nomura Y, Nishiyama N: Autosomal dominant guanosine triphosphate cyclohydrolase I deficiency (Segawa disease). Ann Neurol 54: S32-S45, 2003

33)Lesage S, Drouet V, Majounie E, Deramecourt V, Jacoupy M, et al: Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy. Am J Hum Genet 98: 500-513, 2016

34)Rampoldi L, Dobson-Stone C, Rubio JP, Danek A, Chalmers RM, et al: A conserved sorting-associated protein is mutant in chorea-acanthocytosis. Nat Genet 28: 119-120, 2001

35)Kolehmainen J, Black GC, Saarinen A, Chandler K, Clayton-Smith J, et al: Cohen syndrome is caused by mutations in a novel gene, COH1, encoding a transmembrane protein with a presumed role in vesicle-mediated sorting and intracellular protein transport. Am J Hum Genet 72: 1359-1369, 2003

36)Seong E, Insolera R, Dulovic M, Kamsteeg EJ, Trinh J, Bruggemann N, et al: Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects. Ann Neurol 83: 1075-1088, 2018

37)Gauthier J, Meijer IA, Lessel D, Mencacci NE, Krainc D, et al: Recessive mutations in ＞VPS13D cause childhood onset movement disorders. Ann Neurol 83: 1089-1095, 2018

38)Myers MD, Payne GS: Vps13 and Cdc31/centrin: Puzzling partners in membrane traffic. J Cell Biol 216: 299-301, 2017

39)Quadri M, Mandemakers W, Grochowska MM, Masius R, Geut H, et al: LRP10 genetic variants in familial Parkinson's disease and dementia with Lewy bodies: a genome-wide linkage and sequencing study. Lancet Neurol 17: 597-608, 2018

40)Brodeur J, Thériault C, Lessard-Beaudoin M, Marcil A, Dahan S, et al: LDLR-related protein 10 (LRP10) regulates amyloid precursor protein (APP) trafficking and processing: evidence for a role in Alzheimer's disease. Mol Neurodegener 7: 31, 2012

41)Di Meo I, Tiranti V: Classification and molecular pathogenesis of NBIA syndromes. Eur J Paediatr Neurol 22: 272-284, 2018

42)Nishioka K, Oyama G, Yoshino H, Li Y, Matsushima T, et al: High frequency of beta-propeller protein-associated neurodegeneration (BPAN) among patients with intellectual disability and young-onset parkinsonism. Neurobiol Aging 36: e9-e15, 2004［doi: 10.1016/j.neurobiolaging.2015.01.020］

43)Morgan NV, Westaway SK, Morton JE, Gregory A, Gissen P, et al: PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Nat Genet 38: 752-754, 2006

44)Wang ZB, Liu JY, Xu XJ, Mao XY, Zhang W, et al: Neurodegeneration with brain iron accumulation: Insights into the mitochondria dysregulation. Biomed Pharmacother 118: 109068［doi: 10.1016/j.biopha.2019.109068］

45)Defendini R, Markesbery WR, Mastri AR, Duffy PE: Hallervorden-Spatz disease and infantile neuroaxonal dystrophy. Ultrastructural observations, anatomical pathology and nosology. J Neurol Sci 20: 7-23, 1973

46)Miike T, Ohtani Y, Nishiyama S, Matsuda I: Pathology of skeletal muscle and intramuscular nerves in infantile neuroaxonal dystrophy. Acta neuropathol 69: 117-123, 1986

47)Guo YP, Tang BS, Guo JF: PLA2G6-Associated Neurodegeneration (PLAN): Review of Clinical Phenotypes and Genotypes. Front Neurol 9: 1100, 2018［doi: 10.3389/fneur.2018.01100］

48)Paisan-Ruiz C, Bhatia KP, Li A, Hernandez D, Davis M, et al: Characterization of PLA2G6 as a locus for dystonia-parkinsonism. Ann Neurol 65: 19-23, 2009

49)Paisán-Ruiz C, Li A, Schneider SA, Holton JL, Johnson R, et al: Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations. Neurobiol Aging 33: 814-823, 2012

50)Miki Y, Yoshizawa T, Morohashi S, Seino Y, Kijima H, et al: Neuropathology of PARK14 is identical to idiopathic Parkinson's disease. Mov Disord 32: 799-800, 2017

51)Shinzawa K, Sumi H, Ikawa M, Matsuoka Y, Okabe M, et al: Neuroaxonal dystrophy caused by group VIA phospholipase A2 deficiency in mice: a model of human neurodegenerative disease. J Neurosci 28: 2212-2220, 2008

52)Malik I, Turk J, Mancuso DJ, Montier L, Wohltmann M, et al: Disrupted membrane homeostasis and accumulation of ubiquitinated proteins in a mouse model of infantile neuroaxonal dystrophy caused by PLA2G6 mutations. Am J Pathol 172: 406-416, 2008

53)Zhao Z, Wang J, Zhao C, Bi W, Yue Z, et al: Genetic ablation of PLA2G6 in mice leads to cerebellar atrophy characterized by Purkinje cell loss and glial cell activation. PlOS ONE 6: e26991, 2011［doi: 10.1371/journal.pone.0026991］

54)Koh K, Ichinose Y, Ishiura H, Nan H, Mitsui J, et al: PLA2G6-associated neurodegeneration presenting as a complicated form of hereditary spastic paraplegia. J Hum Genet 64: 55-59, 2019

55)Funayama M, Ohe K, Amo T, Furuya N, Yamaguchi J, et al: CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study. Lancet Neurol 14: 274-282, 2015

56)Ikeda A, Matsushima T, Daida K, Nakajima S, Conedera S, et al: A novel mutation of CHCHD2 p.R8H in a sporadic case of Parkinson's disease. Parkinsonism Relat Disord 34: 66-68, 2017

57)Ogaki K, Koga S, Heckman MG, Fiesel FC, Ando M, et al: Mitochondrial targeting sequence variants of the CHCHD2 gene are a risk for Lewy body disorders. Neurology 85: 2016-2025, 2015

58)Bannwarth S, Ait-El-Mkadem S, Chaussenot A, Genin EC, Lacas-Gervais S, et al: A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement. Brain 137: 2329-2345, 2014

59)Chaussenot A, Le Ber I, Ait-El-Mkadem S, Camuzat A, de Septenville A, et al: Screening of CHCHD10 in a French cohort confirms the involvement of this gene in frontotemporal dementia with amyotrophic lateral sclerosis patients. Neurobiol Aging 35: e1-e4, 2014［doi: 10.1016/j.neurobiolaging.2014.07.022］

60)Johnson JO, Glynn SM, Gibbs JR, Nalls MA, Sabatelli M, et al: Mutations in the CHCHD10 gene are a common cause of familial amyotrophic lateral sclerosis. Brain 137: e311, 2014［doi: 10.1093/brain/awu265］

61)Chiò A, Mora G, Sabatelli M, Caponnetto C, Traynor BJ, et al: CHCH10 mutations in an Italian cohort of familial and sporadic amyotrophic lateral sclerosis patients. Neurobiol Aging 36: e3-e6, 2015［doi: 10.1016/j.neurobiolaging.2015.01.017］

62)Dols-Icardo O, Nebot I, Gorostidi A, Ortega-Cubero S, Hernández I, et al: Analysis of the CHCHD10 gene in patients with frontotemporal dementia and amyotrophic lateral sclerosis from Spain. Brain 138: e400, 2015［doi: 10.1093/brain/awv175］

63)Woo JA, Liu T, Trotter C, Fang CC, De Narvaez E, et al: Loss of function CHCHD10 mutations in cytoplasmic TDP-43 accumulation and synaptic integrity. Nat Commun 8: 15558, 2017［doi: 10.1038/ncomms15558］

64)Burstein SR, Valsecchi F, Kawamata H, Bourens M, Zeng R, et al: In vitro and in vivo studies of the ALS-FTLD protein CHCHD10 reveal novel mitochondrial topology and protein interactions. Hum Mol Genet 27: 160-177, 2018

65)Project MinE ALS Sequencing Consortium: CHCHD10 variants in amyotrophic lateral sclerosis: Where is the evidence? Ann Neurol 84: 110-116, 2018

66)Sidransky E: Gaucher disease: complexity in a “simple” disorder. Mol Genet Metab 83: 6-15, 2004

67)Nishioka K, Vilariño-Güell C, Cobb SA, Kachergus JM, Ross OA, et al: Glucocerebrosidase mutations are not a common risk factor for Parkinson disease in North Africa. Neurosci Lett 477: 57-60, 2010

68)Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, et al: Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N Engl J Med 361: 1651-1661, 2009

69)Li Y, Sekine T, Funayama M, Li L, Yoshino H, et al: Clinicogenetic study of GBA mutations in patients with familial Parkinson's disease. Neurobiol Aging 35: e3-e8, 2014［doi: 10.1016/j.neurobiolaging.2013.09.019］

70)Nishioka K, Ross OA, Vilariño-Güell C, Cobb SA, Kachergus JM, et al. Glucocerebrosidase mutations in diffuse Lewy body disease. Parkinsonism Relat Disord 17: 55-57, 2011

71)Mitsui J, Mizuta I, Toyoda A, Ashida R, Takahashi Y, et al: Mutations for Gaucher disease confer high susceptibility to Parkinson disease. Arch Neurol 66: 571-576, 2009

72)Cilia R, Tunesi S, Marotta G, Cereda E, Siri C, et al: Survival and dementia in GBA-associated Parkinson's disease: The mutation matters. Ann Neurol 80: 662-673, 2016

73)Brockmann K, Srulijes K, Pflederer S, Hauser AK, Schulte C, et al: GBA-associated Parkinson's disease: reduced survival and more rapid progression in a prospective longitudinal study. Mov Disord 30: 407-411, 2015

74)Nalls MA, Duran R, Lopez G, Kurzawa-Akanbi M, McKeith IG, et al: A multicenter study of glucocerebrosidase mutations in dementia with Lewy bodies. JAMA neurol 70: 727-735, 2013

75)Mazzulli JR, Xu YH, Sun Y, Knight AL, McLean PJ, et al: Gaucher disease glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 146: 37-52, 2011

76)Cooper AA, Gitler AD, Cashikar A, Haynes CM, Hill KJ, et al: Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models. Science 313: 324-328, 2006

77)Ikeda A, Shimada H, Nishioka K, Takanashi M, Hayashida A, et al: Clinical heterogeneity of frontotemporal dementia and Parkinsonism linked to chromosome 17 caused by MAPT N279K mutation in relation to tau positron emission tomography features. Mov Disord 34: 568-574, 2019