帕金森病相关基因功能研究进展

doi:10.3724/SP.J.1005.2010.00779

遗传 ›› 2010, Vol. 32 ›› Issue (8): 779-784.doi: 10.3724/SP.J.1005.2010.00779

帕金森病相关基因功能研究进展

王香明, 王丹巧, 汪晓燕

中国中医科学院医学实验中心, 北京 100700

收稿日期:2009-11-24 修回日期:2010-03-19 出版日期:2010-08-20 发布日期:2010-08-23
通讯作者: 王丹巧 E-mail:dq_wang96@hotmail.com
基金资助:
国家自然科学基金项目(编号：03772780)和中国中医科学院基本科研业务费课题项目(编号：ZZ2007011)资助

Function study advances of Parkinson¢s disease related genes

WANG Xiang-Ming, WANG Dan-Qiao, WANG Xiao-Yan

China Academy of Chinese Medical Science, the Experimental Research Center, Beijing 100700, China

Received:2009-11-24 Revised:2010-03-19 Online:2010-08-20 Published:2010-08-23
Contact: WANG Dan-Qiao E-mail:dq_wang96@hotmail.com

摘要/Abstract

摘要： 帕金森病(Parkinson’s disease, PD )是一种较为常见的锥体外系疾病, 主要症状是运动减少、肌强直和震颤; 主要病理特征是黑质致密区多巴胺神经元缺失, 剩余神经元含有Lewy小体。PD的发病机制尚未完全清楚, 一般认为与年龄及环境因素相关。近年来PD遗传学研究取得了长足的进步, 确定了遗传因素在PD发病过程中的重要作用, 发现并鉴定了多个与帕金森病相关的基因: SNCA、LRRK、PINK1、parkin、DJ1和UCHL1等。文章对上述相关基因的功能研究进展进行综述, 为进一步探讨PD发病机制提供参考。

关键词: 基因功能, 分子机制, 帕金森病, 遗传

Abstract: Parkinson¢s disease (PD) is a common extrapyramidal disease, of which the cardinal symptoms are hypokinesia, muscular rigidity, and tremor. The main pathological characteristics of this disease are loss of dopamine neurons in substantia nigra pars compacta, and residual neurons often contain Lewy bodies. The PD pathogenesis is still not well known, while it is generally recognized that age and environmental factors participate in it. In recent years, genetic research on PD has made considerable progresses that genetic factors play important roles on the pathogenesis of PD, and multiple PD related genes, such as SNCA, LRRK2, PINK1, parkin, UCHL1, and DJ1, have been identified. This article summarizes recent progresses on these genes to provide reference for PD study.

Key words: genetics, gene function, molecular mechanism, Parkinson’s disease

王香明，王丹巧，汪晓燕. 帕金森病相关基因功能研究进展[J]. 遗传, 2010, 32(8): 779-784.

WANG Xiang-Meng, WANG Dan-Qiao, HONG Xiao-Yan. Function study advances of Parkinson¢s disease related genes[J]. HEREDITAS, 2010, 32(8): 779-784.

参考文献

[1] Lang AE, Lozano AM. Parkinson’s disease. First of two parts. N Engl J Med, 1998, 339(15): 1044–1053. [2] Papapetropoulos S, Adi N, Ellul J, Argyriou AA, Chroni E. A prospective study of familial versus sporadic Parkin- son's disease. Neurodegener Dis, 2007, 4(6): 424–427. [3] Moore DJ, West AB, Dawson VL, Dawson TM. Molecular pathophysiology of Parkinson's disease. Annu Rev Neurosci, 2005, 28: 57–87. [4] Farrer MJ. Genetics of Parkinson disease: paradigm shifts and future prospects. Nat Rev Genet, 2006, 7(4): 306–318. [5] van der Putten H, Wiederhold KH, Probst A, Barbieri S, Mistl C, Danner S, Kauffmann S, Hofele K, Spooren WP, Ruegg MA, Lin S, Caroni P, Sommer B, Tolnay M, Bilbe G. Neuropathology in mice expressing human alpha-synu clein. J Neurosci, 2000, 20(16): 6021–6029. [6] Feany MB, Bender WW. A Drosophila model of Parkin- son's disease. Nature, 2000, 404(6776): 394–398. [7] Kuwahara T, Koyama A, Gengyo-Ando K, Masuda M, Kowa H, Tsunoda M, Mitani S, Iwatsubo T. Familial Parkinson mutant alpha-synuclein causes dopamine neuron dysfunction in transgenic Caenorhabditis elegans. J Biol Chem, 2006, 281 (1): 334–340. [8] Vartiainen S, Pehkonen P, Lakso M, Nass R, Wong G. Identification of gene expression changes in transgenic C. elegans overexpressing human alpha-synuclein. Neurobiol Dis, 2006, 22(3): 477–486. [9] Kuwahara T, Koyama A, Koyama S, Yoshina S, Ren CH, Kato T, Mitani S, Iwatsubo T. A systematic RNAi screen reveals involvement of endocytic pathway in neuronal dysfunction in alpha-synuclein transgenic C. elegans. Hum Mol Genet, 2008, 17(19): 2997–3009. [10] MacLeod D, Dowman J, Hammond R, Leete T, Inoue K, Abeliovich A. The familial Parkinsonism gene LRRK2 regulates neurite process morphology. Neuron, 2006, 52(4): 587–593. [11] Shin N, Jeong H, Kwon J, Heo HY, Kwon JJ, Yun HJ, Kim CH, Han BS, Tong Y, Shen J, Hatano T, Hattori N, Kim KS, Chang S, Seol W. LRRK2 regulates synaptic vesicle endocytosis. Exp Cell Res, 2008, 314(10): 2055–2065. [12] Gloeckner CJ, Schumacher A, Boldt K, Ueffing M. The Parkinson disease-associated protein kinase LRRK2 ex- hibits MAPKKK activity and phosphorylates MKK3/6 and MKK4/7, in vitro. J Neurochem, 2009, 109(4): 959–968. [13] Milosevic J, Schwarz SC, Ogunlade V, Meyer AK, Storch A, Schwarz J. Emerging role of LRRK2 in human neural progenitor cell cycle progression, survival and differentiation. Mol Neurodegener, 2009, 4: 25. [14] Gillardon F. Leucine-rich repeat kinase 2 phosphorylates brain tubulin-beta isoforms and modulates microtubule stability-a point of convergence in Parkinsonian neurode- generation? J Neurochem, 2009, 110(5): 1514–1522. [15] Alegre-Abarrategui J, Christian H, Lufino M, Mutihac R, Lourenco Venda L, Ansorge O, Wade-Martins R. LRRK2 regulates autophagic activity and localises to specific mem- brane microdomains in a novel human genomic reporter cel lular model. Hum Mol Genet, 2009, 18(21): 4022–4034. [16] Qing H, Wong W, McGeer EG, McGeer PL. Lrrk2 phos- phorylates alpha synuclein at serine 129: Parkinson dis- ease implications. Biochem Biophys Res Commun, 2009, 387(1): 149–152. [17] Li Y, Liu W, Oo TF, Wang L, Tang Y, Jackson-Lewis V, Zhou C, Geghman K, Bogdanov M, Przedborski S, Beal MF, Burke RE, Li C. Mutant LRRK2(R1441G) BAC transgenic mice recapitulate cardinal features of Parkin- son's disease. Nat Neurosci, 2009, 12(7): 826–828. [18] Liu Z, Wang X, Yu Y, Li X, Wang T, Jiang H, Ren Q, Jiao Y, Sawa A, Moran T, Ross CA, Montell C, Smith WW. A Drosophila model for LRRK2-linked Parkinsonism. Proc Natl Acad Sci USA, 2008, 105(7): 2693–2698. [19] Petit A, Kawarai T, Paitel E, Sanjo N, Maj M, Scheid M, Chen F, Gu Y, Hasegawa H, Salehi-Rad S, Wang L, Ro- gaeva E, Fraser P, Robinson B, St George-Hyslop P, Tandon A. Wild-type PINK1 prevents basal and induced neu- ronal apoptosis, a protective effect abrogated by Parkinson disease-related mutations. J Biol Chem, 2005, 280(40): 34025–3432. [20] Park J, Lee SB, Lee S, Kim Y, Song S, Kim S, Bae E, Kim J, Shong M, Kim JM, Chung J. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature, 2006, 441(7097): 1157–1161. [21] Wang D, Qian L, Xiong H, Liu J, Neckameyer WS, Oldham S, Xia K, Wang J, Bodmer R, Zhang Z. Antioxidants protect PINK1-dependent dopaminergic neurons in Drosophila. Proc Natl Acad Sci USA, 2006, 103(36): 13520–13525. [22] Pridgeon JW, Olzmann JA, Chin LS, Li L. PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1. PLoS Biol, 2007, 5(7): e172. [23] Plun-Favreau H, Klupsch K, Moisoi N, Gandhi S, Kjaer S, Frith D, Harvey K, Deas E, Harvey RJ, McDonald N, Wood NW, Martins LM, Downward J. The mitochondrial protease HtrA2 is regulated by Parkinson's dis-ease-associated kinase PINK1. Nat Cell Biol, 2007, 9(11): 1243–1252. [24] Yang Y, Ouyang Y, Yang L, Beal MF, McQuibban A, Vo-gel H, Lu B. Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery. Proc Natl Acad Sci USA, 2008, 105(19): 7070–7075. [25] Cha GH, Kim S, Park J, Lee E, Kim M, Lee SB, Kim JM, Chung J, Cho KS. Parkin negatively regulates JNK path-way in the dopaminergic neurons of Drosophila. Proc Natl Acad Sci USA, 2005, 102(29): 10345–10350. [26] Jiang H, Jiang Q, Liu W, Feng J. Parkin suppresses the expression of monoamine oxidases. J Biol Chem, 2006, 281(13): 8591–8599. [27] Henn IH, Bouman L, Schlehe JS, Schlierf A, Schramm JE, Wegener E, Nakaso K, Culmsee C, Berninger B, Krappmann D, Tatzelt J, Winklhofer KF. Parkin mediates neuroprotection through activation of IkappaB kinase/nu-clear factor-kappaB signaling. J Neurosci, 2007, 27 (8): 1868–1878. [28] Hasegawa T, Treis A, Patenge N, Fiesel FC, Springer W, Kahle PJ. Parkin protects against tyrosinase-mediated dopa-mine neurotoxicity by suppressing stress-activated protein kinase pathways. J Neurochem, 2008, 105(5): 1700–1715. [29] Berger AK, Cortese GP, Amodeo KD, Weihofen A, Letai AG, Lavoie MJ. Parkin Selectively Alters the Intrinsic Threshold for Mitochondrial Cytochrome C Release. Hum Mol Genet, 2009, 18(22): 4317–4328. [30] Burns MP, Zhang L, Rebeck GW, Querfurth HW, Moussa CE. Parkin promotes intracellular Abeta1-42 clearance. Hum Mol Genet, 2009, 18(17): 3206–3216. [31] Kao SY. Regulation of DNA repair by parkin. Biochem Biophys Res Commun, 2009, 382(2): 321–325. [32] Ren Y, Jiang H, Yang F, Nakaso K, Feng J. Parkin protects dopaminergic neurons against microtubule-depolymerizing toxins by attenuating microtubule-associated protein kinase activation. J Biol Chem, 2009, 284(6): 4009–4017. [33] Sandebring A, Dehvari N, Perez-Manso M, Thomas KJ, Karpilovski E, Cookson MR, Cowburn RF, Ce dazo- Minguez A. Parkin deficiency disrupts calcium ho- meostasis by modulating phospholipase C signalling. FEBS J, 2009, 276(18): 5041–5052. [34] Junn E, Taniguchi H, Jeong BS, Zhao X, Ichijo H, Moura- dian MM. Interaction of DJ-1 with Daxx inhibits apoptosis signal-regulating kinase 1 activity and cell death. Proc Natl Acad Sci USA, 2005, 102(27): 9691–9696. [35] Clements CM, McNally RS, Conti BJ, Mak TW, Ting JP. DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Proc Natl Acad Sci USA, 2006, 103(41): 15091–15096. [36] Sekito A, Koide-Yoshida S, Niki T, Taira T, Iguchi-Ariga SM, Ariga H. DJ-1 interacts with HIPK1 and affects H2O2-induced cell death. Free Radic Res, 2006, 40(2): 155–165. [37] Zhong N, Kim CY, Rizzu P, Geula C, Porter DR, Pothos EN, Squitieri F, Heutink P, Xu J. DJ-1 transcriptionally up-regulates the human tyrosine hydroxylase by inhibiting the sumoylation of pyrimidine tract-binding protein-associated splicing factor. J Biol Chem, 2006, 281(30): 20940–20948. [38] Mo JS, Kim MY, Ann EJ, Hong JA, Park HS. DJ-1 modu-lates UV-induced oxidative stress signaling through the suppression of MEKK1 and cell death. Cell Death Differ, 2008, 15(6): 1030–1041. [39] Gu L, Cui T, Fan C, Zhao H, Zhao C, Lu L, Yang H. In-volvement of ERK1/2 signaling pathway in DJ-1-induced neuroprotection against oxidative stress. Biochem Biophys Res Commun, 2009, 383(4): 469–474. [40] Vasseur S, Afzal S, Tardivel-Lacombe J, Park DS, Iovanna JL, Mak TW. DJ-1/PARK7 is an important mediator of hypoxia-induced cellular responses. Proc Natl Acad Sci USA, 2009, 106(4): 1111–1116. [41] Maraganore DM, Lesnick TG, Elbaz A, Chartier-Harlin MC, Gasser T, Kruger R, Hattori N, Mellick GD, Quat-trone A, Satoh J, Toda T, Wang J, Ioannidis JP, de Andrade M, Rocca WA. UCHL1 is a Parkinson's disease suscepti-bility gene. Ann Neurol, 2004, 55(4): 512–521.

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Function study advances of Parkinson¢s disease related genes

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