臨床検査50巻10号

2006年10月発行

今月の主題 認知症の動的神経病理 話題

Familial PD

著者： 小尾智一¹

所属機関： ¹独立行政法人国立病院機構静岡てんかん・神経医療センター神経内科

ページ範囲：P.1165 - P.1170

1．はじめに

　パーキンソン病はアルツハイマー病に次いで多い神経変性疾患である．現在，人口10万人あたり100～150人の有病率で，全国では約12万人が罹患している．パーキンソン病の原因には不明な点が多いが，最近の10年間でメンデル遺伝形式に従う家族性パーキンソン病の遺伝子が同定され(表1)，パーキンソン病の病態メカニズムについての知見が大きく広がった．その存在が確実な遺伝子はα-synuclein，Parkin，DJ-1，PINK，LRRK2である．そして，ほぼ確実なUCHL1と，linkage analysisでその存在が示唆されているPARK3，9，10，11が挙げられる．これらはパーキンソン病の診断と病態の解明に大きく寄与するものと思われ，これまで報告のあった家族性パーキンソン病の遺伝子と臨床像について概説する．

参考文献

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

　２) Kruger R, Kuhn W, Muller T, et al：Ala30Pro mutation in the gene encoding α-synuclein in Parkinson's disease. Nat Genet　18：106-108, 1998

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

　４) Singleton AB, Farrer M, Johnson J, et al：α-Synuclein locus triplication causes Parkinson's disease. Science　302：841, 2003

　５) Muenter MD, Forno LS, Hornykiewicz O, et al：Hereditary form of parkinsonism-dementia. Ann Neurol　43：768-781, 1998

　６) Ibanez P, Bonnet A-M, Debarges B, et al：Causal relation between α-synuclein gene duplication and familial Parkinson's disease. Lancet　364：1169-1171, 2004

　７) Nishioka K, Hayashi S, Matthew J, et al：Clinical Heterogeneity of α-Synuclein Gene Duplication in Parkinson's Disease. Ann Neurol　59：298-309, 2006

　８) Mizuta I, Satake W, Nakabayashi Y, et al：Multiple candidate gene analysis identifies a-synuclein as a susceptibility gene for sporadic Parkinson's disease. Hum Mol Gen (in press)

　８) Mizuta I, Satake W, Nakabayashi Y, et al：Multiple candidate gene analysis identifies a-synuclein as a susceptibility gene for sporadic Parkinson's disease. Hum Mol Gen (in press)

　10) Singleton A, Gwinn-Hardy K, Sharabi Y, et al：Association beween cardiac denervation and parkinsonism caused by α-synuclein gene triplication. Brain　127：768-772, 2004

　11) Kitada T, Asakawa S, Hattori N, et al：Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature　392：605-608, 1998

　12) Lohmann E, Periquet M, Bonifati V, et al：for the French Parkinson's Disease Genetics Study Group, European Consortium on Genetic Susceptibility in Parkinson's Disease. How much phenotypic variation can be attributed to parkin genotype? Ann Neurol　54：176-185, 2003

　13) Shimura H, Hattori N, Kubo S, et al：Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet　25：302-305, 2000

　14) Kann M, Jacobs H, Mohrmann K, et al：Role of parkin mutations in 111 community based patients with early-onset parkinsonism. Ann Neurol　51：621-625, 2002

　15) Lucking CB, Durr A, Bonifati V, et al：Association between early onset Parkinson's disease and mutations in the parkin gene. N Engl J Med　342：1560-1567, 2000

　16) Abbas N, Lucking CB, Ricard S, et al：A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. Hum Mol Genet　8：567-574, 1999

　17) Oliveira SA, Scott WK, Martin ER, et al：Parkin mutations and susceptibility alleles in late-onset Parkinson's disease. Ann Neurol　53：624-629, 2003

　18) Valente EM, Abou-Sleiman PM, Caputo V, et al：Hereditary early onset Parkinson's disease is caused by mutations in PINK1. Science　304：1158-1160, 2004

　19) Rohe CF, Montagna P, Breedveld G, et al：Homozygous PINK1 C-terminus mutation causing early-onset parkinsonism. Ann Neurol　56：427-431, 2004

　20) Hatano Y, Li Y, Sato K, et al：Novel PINK1 mutations in early-onset parkinsonism. Ann Neurol　56：424-427, 2004

　21) Valente EM, Salvi S, Ialongo T, et al：PINK1 mutations are associated with sporadic early-onset parkinsonism. Ann Neurol　56：336-341, 2004

　22) Bonifati V, Rizzu P, van Baren MJ, et al：Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science　299：256-259, 2003

　23) Canet-Aviles RM, Wilson MA, Miller DW, et al：The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proc Natl Acad Sci USA　101：9103-9108, 2004

　24) Abou-Sleiman PM, Healy DG, Quinn N, et Al：The role of pathogenic DJ-1 mutations in Parkinson's disease. Ann Neurol　54：283-286, 2003

　25) Hasegawa K, Kowa H：Autosomal dominant familial Parkinson disease：older onset of age, and good response to levodopa therapy. Europ Neurol　38 (suppl. 1)：39-43, 1997

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

　27) Funayama M, Hasegawa K, Ohta E, et al：An LRRK2 Mutation as a Cause for the Parkinsonism in the Original PARK8 Family. Ann Neurol　57：918-921, 2005

　28) West AB, Moore DJ, Biskup S, et al：Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci USA　102：16535-16536,2005

　29) Giasson BI, Covy JP, Bonini NM, et al：Biochemical and pathological characterization of Lrrk2. Ann Neurol　59：315-322, 2006

　30) Ross OA, Toft M, Whittle AJ, et al：Lrrk2 and Lewy body disease. Ann Neurol　59：388-393, 2006

　31) Leroy E, Boyer R, Auburger G, et al：The ubiquitin pathway in Parkinson's disease. Nature　395：451-452, 1998