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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 吳瑞美(Ruey-Meei Wu) | |
dc.contributor.author | Meng-Ling Chen | en |
dc.contributor.author | 陳孟伶 | zh_TW |
dc.date.accessioned | 2021-07-10T22:02:50Z | - |
dc.date.available | 2021-07-10T22:02:50Z | - |
dc.date.copyright | 2018-09-18 | |
dc.date.issued | 2018 | |
dc.date.submitted | 2018-09-12 | |
dc.identifier.citation | Aasly JO, Vilarino-Guell C, Dachsel JC, Webber PJ, West AB, Haugarvoll K, Johansen KK, Toft M, Nutt JG, Payami H, Kachergus JM, Lincoln SJ, Felic A, Wider C, Soto-Ortolaza AI, Cobb SA, White LR, Ross OA, Farrer MJ (2010) Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson's disease. Mov Disord 25:2156-2163.
Abe T, Langenick J, Williams JG (2003) Rapid generation of gene disruption constructs by in vitro transposition and identification of a Dictyostelium protein kinase that regulates its rate of growth and development. Nucleic Acids Res 31:e107. Abysalh JC, Kuchnicki LL, Larochelle DA (2003) The identification of pats1, a novel gene locus required for cytokinesis in Dictyostelium discoideum. Mol Biol Cell 14:14-25. Ahmed I, Liang Y, Schools S, Dawson VL, Dawson TM, Savitt JM (2012) Development and characterization of a new Parkinson's disease model resulting from impaired autophagy. J Neurosci 32:16503-16509. Alegre-Abarrategui J, Christian H, Lufino MM, Mutihac R, Venda LL, Ansorge O, Wade-Martins R (2009) LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model. Hum Mol Genet 18:4022-4034. Anand VS, Reichling LJ, Lipinski K, Stochaj W, Duan W, Kelleher K, Pungaliya P, Brown EL, Reinhart PH, Somberg R, Hirst WD, Riddle SM, Braithwaite SP (2009) Investigation of leucine-rich repeat kinase 2 : enzymological properties and novel assays. FEBS J 276:466-478. Antony PM, Diederich NJ, Kruger R, Balling R (2013) The hallmarks of Parkinson's disease. FEBS J 280:5981-5993. Bahnassawy L, Nicklas S, Palm T, Menzl I, Birzele F, Gillardon F, Schwamborn JC (2013) The parkinson's disease-associated LRRK2 mutation R1441G inhibits neuronal differentiation of neural stem cells. Stem Cells Dev 22:2487-2496. Benamer HT, de Silva R (2010) LRRK2 G2019S in the North African population: a review. Eur Neurol 63:321-325. Berger Z, Smith KA, Lavoie MJ (2010) Membrane localization of LRRK2 is associated with increased formation of the highly active LRRK2 dimer and changes in its phosphorylation. Biochemistry 49:5511-5523. Berridge MJ, Bootman MD, Roderick HL (2003) Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 4:517-529. Bogaerts V, Nuytemans K, Reumers J, Pals P, Engelborghs S, Pickut B, Corsmit E, Peeters K, Schymkowitz J, De Deyn PP, Cras P, Rousseau F, Theuns J, Van Broeckhoven C (2008) Genetic variability in the mitochondrial serine protease HTRA2 contributes to risk for Parkinson disease. Hum Mutat 29:832-840. Bosgraaf L, Russcher H, Smith JL, Wessels D, Soll DR, Van Haastert PJ (2002) A novel cGMP signalling pathway mediating myosin phosphorylation and chemotaxis in Dictyostelium. EMBO J 21:4560-4570. Bosgraaf L, Van Haastert PJ (2003) Roc, a Ras/GTPase domain in complex proteins. Biochim Biophys Acta 1643:5-10. Chang CR, Blackstone C (2010) Dynamic regulation of mitochondrial fission through modification of the dynamin-related protein Drp1. Ann N Y Acad Sci 1201:34-39. Chang XL, Mao XY, Li HH, Zhang JH, Li NN, Burgunder JM, Peng R, Tan EK (2011) Association of GWAS loci with PD in China. Am J Med Genet B Neuropsychiatr Genet 156B:334-339. Chaudhuri KR, Healy DG, Schapira AH, National Institute for Clinical E (2006) Non-motor symptoms of Parkinson's disease: diagnosis and management. Lancet Neurol 5:235-245. Chen CM, Wu CH, Hsieh CH, Lin CH, Chen IC, Chen YC, Lee LC, Lee CM, Tseng YC, Lee-Chen GJ, Wu YR (2014) HTRA2 variations in Taiwanese Parkinson's disease. J Neural Transm (Vienna) 121:491-498. Chen ML, Wu RM (2018) LRRK2 gene mutations in the pathophysiology of the ROCO domain and therapeutic targets for Parkinson's disease: a review. J Biomed Sci 25:52. Consortium UKPsD, Wellcome Trust Case Control C, Spencer CC, Plagnol V, Strange A, Gardner M, Paisan-Ruiz C, Band G, Barker RA, Bellenguez C, Bhatia K, Blackburn H, Blackwell JM, Bramon E, Brown MA, Brown MA, Burn D, Casas JP, Chinnery PF, Clarke CE, Corvin A, Craddock N, Deloukas P, Edkins S, Evans J, Freeman C, Gray E, Hardy J, Hudson G, Hunt S, Jankowski J, Langford C, Lees AJ, Markus HS, Mathew CG, McCarthy MI, Morrison KE, Palmer CN, Pearson JP, Peltonen L, Pirinen M, Plomin R, Potter S, Rautanen A, Sawcer SJ, Su Z, Trembath RC, Viswanathan AC, Williams NW, Morris HR, Donnelly P, Wood NW (2011) Dissection of the genetics of Parkinson's disease identifies an additional association 5' of SNCA and multiple associated haplotypes at 17q21. Hum Mol Genet 20:345-353. Dachsel JC, Taylor JP, Mok SS, Ross OA, Hinkle KM, Bailey RM, Hines JH, Szutu J, Madden B, Petrucelli L, Farrer MJ (2007) Identification of potential protein interactors of Lrrk2. Parkinsonism Relat Disord 13:382-385. Dauer W, Przedborski S (2003) Parkinson's disease: mechanisms and models. Neuron 39:889-909. De Michele G, Filla A, Volpe G, De Marco V, Gogliettino A, Ambrosio G, Marconi R, Castellano AE, Campanella G (1996) Environmental and genetic risk factors in Parkinson's disease: a case-control study in southern Italy. Mov Disord 11:17-23. Deng H, Wang P, Jankovic J (2018) The genetics of Parkinson disease. Ageing Res Rev 42:72-85. Di Fonzo A, Rohe CF, Ferreira J, Chien HF, Vacca L, Stocchi F, Guedes L, Fabrizio E, Manfredi M, Vanacore N, Goldwurm S, Breedveld G, Sampaio C, Meco G, Barbosa E, Oostra BA, Bonifati V, Italian Parkinson Genetics N (2005) A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease. Lancet 365:412-415. Dorsey ER, Constantinescu R, Thompson JP, Biglan KM, Holloway RG, Kieburtz K, Marshall FJ, Ravina BM, Schifitto G, Siderowf A, Tanner CM (2007) Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology 68:384-386. Edwards TL, Scott WK, Almonte C, Burt A, Powell EH, Beecham GW, Wang L, Zuchner S, Konidari I, Wang G, Singer C, Nahab F, Scott B, Stajich JM, Pericak-Vance M, Haines J, Vance JM, Martin ER (2010) Genome-wide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson disease. Ann Hum Genet 74:97-109. Fan TS, Wu RM, Chen PL, Chen TF, Li HY, Lin YH, Chen CY, Chen ML, Tai CH, Lin HI, Lin CH (2016) Clinical heterogeneity of LRRK2 p.I2012T mutation. Parkinsonism Relat Disord 33:36-43. Farrer MJ, Stone JT, Lin CH, Dachsel JC, Hulihan MM, Haugarvoll K, Ross OA, Wu RM (2007) Lrrk2 G2385R is an ancestral risk factor for Parkinson's disease in Asia. Parkinsonism Relat Disord 13:89-92. Ferreira JJ, Guedes LC, Rosa MM, Coelho M, van Doeselaar M, Schweiger D, Di Fonzo A, Oostra BA, Sampaio C, Bonifati V (2007) High prevalence of LRRK2 mutations in familial and sporadic Parkinson's disease in Portugal. Mov Disord 22:1194-1201. Firestone JA, Smith-Weller T, Franklin G, Swanson P, Longstreth WT, Jr., Checkoway H (2005) Pesticides and risk of Parkinson disease: a population-based case-control study. Arch Neurol 62:91-95. Friedman LG, Lachenmayer ML, Wang J, He L, Poulose SM, Komatsu M, Holstein GR, Yue Z (2012) Disrupted autophagy leads to dopaminergic axon and dendrite degeneration and promotes presynaptic accumulation of alpha-synuclein and LRRK2 in the brain. J Neurosci 32:7585-7593. Funayama M, Hasegawa K, Kowa H, Saito M, Tsuji S, Obata F (2002) A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2-q13.1. Ann Neurol 51:296-301. Gaenslen A, Gasser T, Berg D (2008) Nutrition and the risk for Parkinson's disease: review of the literature. J Neural Transm 115:703-713. Gao L, Gomez-Garre P, Diaz-Corrales FJ, Carrillo F, Carballo M, Palomino A, Diaz-Martin J, Mejias R, Vime PJ, Lopez-Barneo J, Mir P (2009) Prevalence and clinical features of LRRK2 mutations in patients with Parkinson's disease in southern Spain. Eur J Neurol 16:957-960. Gardet A, Benita Y, Li C, Sands BE, Ballester I, Stevens C, Korzenik JR, Rioux JD, Daly MJ, Xavier RJ, Podolsky DK (2010) LRRK2 is involved in the IFN-gamma response and host response to pathogens. J Immunol 185:5577-5585. Gibb WR, Lees AJ (1988) The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease. J Neurol Neurosurg Psychiatry 51:745-752. Gilks WP, Abou-Sleiman PM, Gandhi S, Jain S, Singleton A, Lees AJ, Shaw K, Bhatia KP, Bonifati V, Quinn NP, Lynch J, Healy DG, Holton JL, Revesz T, Wood NW (2005) A common LRRK2 mutation in idiopathic Parkinson's disease. Lancet 365:415-416. Glick D, Barth S, Macleod KF (2010) Autophagy: cellular and molecular mechanisms. J Pathol 221:3-12. Gloeckner CJ, Kinkl N, Schumacher A, Braun RJ, O'Neill E, Meitinger T, Kolch W, Prokisch H, Ueffing M (2006) The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity. Hum Mol Genet 15:223-232. Gloeckner CJ, Schumacher A, Boldt K, Ueffing M (2009) The Parkinson disease-associated protein kinase LRRK2 exhibits MAPKKK activity and phosphorylates MKK3/6 and MKK4/7, in vitro. J Neurochem 109:959-968. Goldberg JM, Bosgraaf L, Van Haastert PJ, Smith JL (2002) Identification of four candidate cGMP targets in Dictyostelium. Proc Natl Acad Sci U S A 99:6749-6754. Goldman SM (2014) Environmental toxins and Parkinson's disease. Annu Rev Pharmacol Toxicol 54:141-164. Goldwurm S, Di Fonzo A, Simons EJ, Rohe CF, Zini M, Canesi M, Tesei S, Zecchinelli A, Antonini A, Mariani C, Meucci N, Sacilotto G, Sironi F, Salani G, Ferreira J, Chien HF, Fabrizio E, Vanacore N, Dalla Libera A, Stocchi F, Diroma C, Lamberti P, Sampaio C, Meco G, Barbosa E, Bertoli-Avella AM, Breedveld GJ, Oostra BA, Pezzoli G, Bonifati V (2005) The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinson's disease and originates from a common ancestor. J Med Genet 42:e65. Gorell JM, Peterson EL, Rybicki BA, Johnson CC (2004) Multiple risk factors for Parkinson's disease. J Neurol Sci 217:169-174. Gorostidi A, Ruiz-Martinez J, Lopez de Munain A, Alzualde A, Marti Masso JF (2009) LRRK2 G2019S and R1441G mutations associated with Parkinson's disease are common in the Basque Country, but relative prevalence is determined by ethnicity. Neurogenetics 10:157-159. Gotthardt K, Weyand M, Kortholt A, Van Haastert PJ, Wittinghofer A (2008) Structure of the Roc-COR domain tandem of C. tepidum, a prokaryotic homologue of the human LRRK2 Parkinson kinase. EMBO J 27:2239-2249. Gray CW, Ward RV, Karran E, Turconi S, Rowles A, Viglienghi D, Southan C, Barton A, Fantom KG, West A, Savopoulos J, Hassan NJ, Clinkenbeard H, Hanning C, Amegadzie B, Davis JB, Dingwall C, Livi GP, Creasy CL (2000) Characterization of human HtrA2, a novel serine protease involved in the mammalian cellular stress response. Eur J Biochem 267:5699-5710. Greggio E, Cookson MR (2009) Leucine-rich repeat kinase 2 mutations and Parkinson's disease: three questions. ASN Neuro 1. Greggio E, Jain S, Kingsbury A, Bandopadhyay R, Lewis P, Kaganovich A, van der Brug MP, Beilina A, Blackinton J, Thomas KJ, Ahmad R, Miller DW, Kesavapany S, Singleton A, Lees A, Harvey RJ, Harvey K, Cookson MR (2006) Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiol Dis 23:329-341. Greggio E, Zambrano I, Kaganovich A, Beilina A, Taymans JM, Daniels V, Lewis P, Jain S, Ding J, Syed A, Thomas KJ, Baekelandt V, Cookson MR (2008) The Parkinson disease-associated leucine-rich repeat kinase 2 (LRRK2) is a dimer that undergoes intramolecular autophosphorylation. J Biol Chem 283:16906-16914. Guo JF, Li K, Yu RL, Sun QY, Wang L, Yao LY, Hu YC, Lv ZY, Luo LZ, Shen L, Jiang H, Yan XX, Pan Q, Xia K, Tang BS (2015) Polygenic determinants of Parkinson's disease in a Chinese population. Neurobiol Aging 36:1765 e1761-1765 e1766. Guo L, Gandhi PN, Wang W, Petersen RB, Wilson-Delfosse AL, Chen SG (2007) The Parkinson's disease-associated protein, leucine-rich repeat kinase 2 (LRRK2), is an authentic GTPase that stimulates kinase activity. Exp Cell Res 313:3658-3670. Guo L, Wang W, Chen SG (2006) Leucine-rich repeat kinase 2: relevance to Parkinson's disease. Int J Biochem Cell Biol 38:1469-1475. Haebig K, Gloeckner CJ, Miralles MG, Gillardon F, Schulte C, Riess O, Ueffing M, Biskup S, Bonin M (2010) ARHGEF7 (Beta-PIX) acts as guanine nucleotide exchange factor for leucine-rich repeat kinase 2. PLoS One 5:e13762. Hakimi M, Selvanantham T, Swinton E, Padmore RF, Tong Y, Kabbach G, Venderova K, Girardin SE, Bulman DE, Scherzer CR, LaVoie MJ, Gris D, Park DS, Angel JB, Shen J, Philpott DJ, Schlossmacher MG (2011) Parkinson's disease-linked LRRK2 is expressed in circulating and tissue immune cells and upregulated following recognition of microbial structures. J Neural Transm (Vienna) 118:795-808. Hamza TH, Zabetian CP, Tenesa A, Laederach A, Montimurro J, Yearout D, Kay DM, Doheny KF, Paschall J, Pugh E, Kusel VI, Collura R, Roberts J, Griffith A, Samii A, Scott WK, Nutt J, Factor SA, Payami H (2010) Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease. Nat Genet 42:781-785. Healy DG, Falchi M, O'Sullivan SS, Bonifati V, Durr A, Bressman S, Brice A, Aasly J, Zabetian CP, Goldwurm S, Ferreira JJ, Tolosa E, Kay DM, Klein C, Williams DR, Marras C, Lang AE, Wszolek ZK, Berciano J, Schapira AH, Lynch T, Bhatia KP, Gasser T, Lees AJ, Wood NW, International LC (2008) Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurol 7:583-590. Heo HY, Park JM, Kim CH, Han BS, Kim KS, Seol W (2010) LRRK2 enhances oxidative stress-induced neurotoxicity via its kinase activity. Exp Cell Res 316:649-656. Hernandez DG, Reed X, Singleton AB (2016) Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance. J Neurochem 139 Suppl 1:59-74. Hockey LN, Kilpatrick BS, Eden ER, Lin-Moshier Y, Brailoiu GC, Brailoiu E, Futter CE, Schapira AH, Marchant JS, Patel S (2015) Dysregulation of lysosomal morphology by pathogenic LRRK2 is corrected by TPC2 inhibition. J Cell Sci 128:232-238. Hsu KH, Froines JR, Chen CJ (1997) Studies of arsenic ingestion from drinking water in northeastern Taiwan: chemical speciation and urinary metabolites. In: Arsenic: Exposure and Health Effects(Abernathy, C. O. et al., eds), pp 190-209 London: Springer Netherlands. Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992) Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 55:181-184. Imai Y, Gehrke S, Wang HQ, Takahashi R, Hasegawa K, Oota E, Lu B (2008) Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila. EMBO J 27:2432-2443. Ito G, Okai T, Fujino G, Takeda K, Ichijo H, Katada T, Iwatsubo T (2007) GTP binding is essential to the protein kinase activity of LRRK2, a causative gene product for familial Parkinson's disease. Biochemistry 46:1380-1388. Jaleel M, Nichols RJ, Deak M, Campbell DG, Gillardon F, Knebel A, Alessi DR (2007) LRRK2 phosphorylates moesin at threonine-558: characterization of how Parkinson's disease mutants affect kinase activity. Biochem J 405:307-317. Jones JM, Datta P, Srinivasula SM, Ji W, Gupta S, Zhang Z, Davies E, Hajnoczky G, Saunders TL, Van Keuren ML, Fernandes-Alnemri T, Meisler MH, Alnemri ES (2003) Loss of Omi mitochondrial protease activity causes the neuromuscular disorder of mnd2 mutant mice. Nature 425:721-727. Kachergus J, Mata IF, Hulihan M, Taylor JP, Lincoln S, Aasly J, Gibson JM, Ross OA, Lynch T, Wiley J, Payami H, Nutt J, Maraganore DM, Czyzewski K, Styczynska M, Wszolek ZK, Farrer MJ, Toft M (2005) Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. Am J Hum Genet 76:672-680. Karimi-Moghadam A, Charsouei S, Bell B, Jabalameli MR (2018) Parkinson Disease from Mendelian Forms to Genetic Susceptibility: New Molecular Insights into the Neurodegeneration Process. Cell Mol Neurobiol 38:1153-1178. Kobe B, Deisenhofer J (1995) A structural basis of the interactions between leucine-rich repeats and protein ligands. Nature 374:183-186. Kobe B, Kajava AV (2001) The leucine-rich repeat as a protein recognition motif. Curr Opin Struct Biol 11:725-732. Korolchuk VI, Rubinsztein DC (2011) Regulation of autophagy by lysosomal positioning. Autophagy 7:927-928. Kruger R, Sharma M, Riess O, Gasser T, Van Broeckhoven C, Theuns J, Aasly J, Annesi G, Bentivoglio AR, Brice A, Djarmati A, Elbaz A, Farrer M, Ferrarese C, Gibson JM, Hadjigeorgiou GM, Hattori N, Ioannidis JP, Jasinska-Myga B, Klein C, Lambert JC, Lesage S, Lin JJ, Lynch T, Mellick GD, de Nigris F, Opala G, Prigione A, Quattrone A, Ross OA, Satake W, Silburn PA, Tan EK, Toda T, Tomiyama H, Wirdefeldt K, Wszolek Z, Xiromerisiou G, Maraganore DM, Genetic Epidemiology of Parkinson's disease c (2011) A large-scale genetic association study to evaluate the contribution of Omi/HtrA2 (PARK13) to Parkinson's disease. Neurobiol Aging 32:548 e549-518. Lee MJ, Mata IF, Lin CH, Tzen KY, Lincoln SJ, Bounds R, Lockhart PJ, Hulihan MM, Farrer MJ, Wu RM (2009) Genotype-phenotype correlates in Taiwanese patients with early-onset recessive Parkinsonism. Mov Disord 24:104-108. Lesage S, Condroyer C, Lannuzel A, Lohmann E, Troiano A, Tison F, Damier P, Thobois S, Ouvrard-Hernandez AM, Rivaud-Pechoux S, Brefel-Courbon C, Destee A, Tranchant C, Romana M, Leclere L, Durr A, Brice A, French Parkinson's Disease Genetics Study G (2009) Molecular analyses of the LRRK2 gene in European and North African autosomal dominant Parkinson's disease. J Med Genet 46:458-464. Lesage S, Ibanez P, Lohmann E, Pollak P, Tison F, Tazir M, Leutenegger AL, Guimaraes J, Bonnet AM, Agid Y, Durr A, Brice A, French Parkinson's Disease Genetics Study G (2005) G2019S LRRK2 mutation in French and North African families with Parkinson's disease. Ann Neurol 58:784-787. Lesage S, Patin E, Condroyer C, Leutenegger AL, Lohmann E, Giladi N, Bar-Shira A, Belarbi S, Hecham N, Pollak P, Ouvrard-Hernandez AM, Bardien S, Carr J, Benhassine T, Tomiyama H, Pirkevi C, Hamadouche T, Cazeneuve C, Basak AN, Hattori N, Durr A, Tazir M, Orr-Urtreger A, Quintana-Murci L, Brice A, French Parkinson's Disease Genetics Study G (2010) Parkinson's disease-related LRRK2 G2019S mutation results from independent mutational events in humans. Hum Mol Genet 19:1998-2004. Lewis PA, Greggio E, Beilina A, Jain S, Baker A, Cookson MR (2007) The R1441C mutation of LRRK2 disrupts GTP hydrolysis. Biochem Biophys Res Commun 357:668-671. Li D, Roberts R (2001) WD-repeat proteins: structure characteristics, biological function, and their involvement in human diseases. Cell Mol Life Sci 58:2085-2097. Li JQ, Tan L, Yu JT (2014) The role of the LRRK2 gene in Parkinsonism. Mol Neurodegener 9:47. Li X, Tan YC, Poulose S, Olanow CW, Huang XY, Yue Z (2007) Leucine-rich repeat kinase 2 (LRRK2)/PARK8 possesses GTPase activity that is altered in familial Parkinson's disease R1441C/G mutants. J Neurochem 103:238-247. 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 (2009) Mutant LRRK2(R1441G) BAC transgenic mice recapitulate cardinal features of Parkinson's disease. Nat Neurosci 12:826-828. Lin CH, Chen ML, Chen GS, Tai CH, Wu RM (2011a) Novel variant Pro143Ala in HTRA2 contributes to Parkinson's disease by inducing hyperphosphorylation of HTRA2 protein in mitochondria. Hum Genet 130:817-827. Lin CH, Lin JW, Liu YC, Chang CH, Wu RM (2014) Risk of Parkinson's disease following severe constipation: a nationwide population-based cohort study. Parkinsonism Relat Disord 20:1371-1375. Lin CH, Lin JW, Liu YC, Chang CH, Wu RM (2015) Risk of Parkinson's disease following anxiety disorders: a nationwide population-based cohort study. Eur J Neurol 22:1280-1287. Lin CH, Tan EK, Chen ML, Tan LC, Lim HQ, Chen GS, Wu RM (2008a) Novel ATP13A2 variant associated with Parkinson disease in Taiwan and Singapore. Neurology 71:1727-1732. Lin CH, Tzen KY, Yu CY, Tai CH, Farrer MJ, Wu RM (2008b) LRRK2 mutation in familial Parkinson's disease in a Taiwanese population: clinical, PET, and functional studies. J Biomed Sci 15:661-667. Lin CH, Wu RM, Chang HY, Chiang YT, Lin HH (2013) Preceding pain symptoms and Parkinson's disease: a nationwide population-based cohort study. Eur J Neurol 20:1398-1404. Lin CH, Wu RM, Tai CH, Chen ML, Hu FC (2011b) Lrrk2 S1647T and BDNF V66M interact with environmental factors to increase risk of Parkinson's disease. Parkinsonism & related disorders 17:84-88. Liou AK, Leak RK, Li L, Zigmond MJ (2008) Wild-type LRRK2 but not its mutant attenuates stress-induced cell death via ERK pathway. Neurobiol Dis 32:116-124. Liu WM, Lin RJ, Yu RL, Tai CH, Lin CH, Wu RM (2015) The impact of nonmotor symptoms on quality of life in patients with Parkinson's disease in Taiwan. Neuropsychiatr Dis Treat 11:2865-2873. Lockhart PJ, Bounds R, Hulihan M, Kachergus J, Lincoln S, Lin CH, Wu RM, Farrer MJ (2004) Lack of mutations in DJ-1 in a cohort of Taiwanese ethnic Chinese with early-onset parkinsonism. Mov Disord 19:1065-1069. Lu CS, Simons EJ, Wu-Chou YH, Fonzo AD, Chang HC, Chen RS, Weng YH, Rohe CF, Breedveld GJ, Hattori N, Gasser T, Oostra BA, Bonifati V (2005) The LRRK2 I2012T, G2019S, and I2020T mutations are rare in Taiwanese patients with sporadic Parkinson's disease. Parkinsonism Relat Disord 11:521-522. Lubbe S, Morris HR (2014) Recent advances in Parkinson's disease genetics. J Neurol 261:259-266. Luzon-Toro B, Rubio de la Torre E, Delgado A, Perez-Tur J, Hilfiker S (2007) Mechanistic insight into the dominant mode of the Parkinson's disease-associated G2019S LRRK2 mutation. Hum Mol Genet 16:2031-2039. Malavasi F, Deaglio S, Funaro A, Ferrero E, Horenstein AL, Ortolan E, Vaisitti T, Aydin S (2008) Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. Physiological reviews 88:841-886. Manzoni C, Mamais A, Dihanich S, McGoldrick P, Devine MJ, Zerle J, Kara E, Taanman JW, Healy DG, Marti-Masso JF, Schapira AH, Plun-Favreau H, Tooze S, Hardy J, Bandopadhyay R, Lewis PA (2013) Pathogenic Parkinson's disease mutations across the functional domains of LRRK2 alter the autophagic/lysosomal response to starvation. Biochem Biophys Res Commun 441:862-866. Martin I, Kim JW, Lee BD, Kang HC, Xu JC, Jia H, Stankowski J, Kim MS, Zhong J, Kumar M, Andrabi SA, Xiong Y, Dickson DW, Wszolek ZK, Pandey A, Dawson TM, Dawson VL (2014) Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease. Cell 157:472-485. Martinez-Martin P, Rodriguez-Blazquez C, Kurtis MM, Chaudhuri KR, Group NV (2011) The impact of non-motor symptoms on health-related quality of life of patients with Parkinson's disease. Mov Disord 26:399-406. Mata IF, Kachergus JM, Taylor JP, Lincoln S, Aasly J, Lynch T, Hulihan MM, Cobb SA, Wu RM, Lu CS, Lahoz C, Wszolek ZK, Farrer MJ (2005) Lrrk2 pathogenic substitutions in Parkinson's disease. Neurogenetics 6:171-177. Mehanna R, Moore S, Hou JG, Sarwar AI, Lai EC (2014) Comparing clinical features of young onset, middle onset and late onset Parkinson's disease. Parkinsonism Relat Disord 20:530-534. Miyake Y, Tanaka K, Fukushima W, Kiyohara C, Sasaki S, Tsuboi Y, Yamada T, Oeda T, Shimada H, Kawamura N, Sakae N, Fukuyama H, Hirota Y, Nagai M (2012) Lack of association between BST1 polymorphisms and sporadic Parkinson's disease in a Japanese population. Journal of the neurological sciences 323:162-166. Momodu MA, Anyakora CA (2010) Heavy metal contamination of ground Water: the surulere case study. Research Journal of Environmental and Earth Sciences 2:39-43. Ngim CH, Devathasan G (1989) Epidemiologic study on the association between body burden mercury level and idiopathic Parkinson's disease. Neuroepidemiology 8:128-141. Nichols WC, Pankratz N, Hernandez D, Paisan-Ruiz C, Jain S, Halter CA, Michaels VE, Reed T, Rudolph A, Shults CW, Singleton A, Foroud T, Parkinson Study Group Pi (2005) Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease. Lancet 365:410-412. Niu J, Yu M, Wang C, Xu Z (2012) Leucine-rich repeat kinase 2 disturbs mitochondrial dynamics via Dynamin-like protein. J Neurochem 122:650-658. Orenstein SJ, Kuo SH, Tasset I, Arias E, Koga H, Fernandez-Carasa I, Cortes E, Honig LS, Dauer W, Consiglio A, Raya A, Sulzer D, Cuervo AM (2013) Interplay of LRRK2 with chaperone-mediated autophagy. Nat Neurosci 16:394-406. Paisan-Ruiz C, Jain S, Evans EW, Gilks WP, Simon J, van der Brug M, Lopez de Munain A, Aparicio S, Gil AM, Khan N, Johnson J, Martinez JR, Nicholl D, Carrera IM, Pena AS, de Silva R, Lees A, Marti-Masso JF, Perez-Tur J, Wood NW, Singleton AB (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 44:595-600. Park J, Yoo CI, Sim CS, Kim HK, Kim JW, Jeon BS, Kim KR, Bang OY, Lee WY, Yi Y, Jung KY, Chung SE, Kim Y (2005) Occupations and Parkinson's disease: a multi-center case-control study in South Korea. Neurotoxicology 26:99-105. Plowey ED, Cherra SJ, 3rd, Liu YJ, Chu CT (2008) Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells. J Neurochem 105:1048-1056. 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 (2007) The mitochondrial protease HtrA2 is regulated by Parkinson's disease-associated kinase PINK1. Nat Cell Biol 9:1243-1252. Quarona V, Zaccarello G, Chillemi A, Brunetti E, Singh VK, Ferrero E, Funaro A, Horenstein AL, Malavasi F (2013) CD38 and CD157: A long journey from activation markers to multifunctional molecules. Cytometry B Clin Cytom 84:207-217. Ramonet D, Daher JP, Lin BM, Stafa K, Kim J, Banerjee R, Westerlund M, Pletnikova O, Glauser L, Yang L, Liu Y, Swing DA, Beal MF, Troncoso JC, McCaffery JM, Jenkins NA, Copeland NG, Galter D, Thomas B, Lee MK, Dawson TM, Dawson VL, Moore DJ (2011) Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2. PLoS One 6:e18568. Ray S, Bender S, Kang S, Lin R, Glicksman MA, Liu M (2014) The Parkinson disease-linked LRRK2 protein mutation I2020T stabilizes an active state conformation leading to increased kinase activity. J Biol Chem 289:13042-13053. Ross OA, Soto-Ortolaza AI, Heckman MG, Aasly JO, Abahuni N, Annesi G, Bacon JA, Bardien S, Bozi M, Brice A, Brighina L, Van Broeckhoven C, Carr J, Chartier-Harlin MC, Dardiotis E, Dickson DW, Diehl NN, Elbaz A, Ferrarese C, Ferraris A, Fiske B, Gibson JM, Gibson R, Hadjigeorgiou GM, Hattori N, Ioannidis JP, Jasinska-Myga B, Jeon BS, Kim YJ, Klein C, Kruger R, Kyratzi E, Lesage S, Lin CH, Lynch T, Maraganore DM, Mellick GD, Mutez E, Nilsson C, Opala G, Park SS, Puschmann A, Quattrone A, Sharma M, Silburn PA, Sohn YH, Stefanis L, Tadic V, Theuns J, Tomiyama H, Uitti RJ, Valente EM, van de Loo S, Vassilatis DK, Vilarino-Guell C, White LR, Wirdefeldt K, Wszolek ZK, Wu RM, Farrer MJ, Genetic Epidemiology Of Parkinson's Disease C (2011) Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case-control study. Lancet Neurol 10:898-908. Ross OA, Spanaki C, Griffith A, Lin CH, Kachergus J, Haugarvoll K, Latsoudis H, Plaitakis A, Ferreira JJ, Sampaio C, Bonifati V, Wu RM, Zabetian CP, Farrer MJ (2009) Haplotype analysis of Lrrk2 R1441H carriers with parkinsonism. Parkinsonism Relat Disord 15:466-467. Ross OA, Wu YR, Lee MC, Funayama M, Chen ML, Soto AI, Mata IF, Lee-Chen GJ, Chen CM, Tang M, Zhao Y, Hattori N, Farrer MJ, Tan EK, Wu RM (2008) Analysis of Lrrk2 R1628P as a risk factor for Parkinson's disease. Ann Neurol 64:88-92. Saad M, Lesage S, Saint-Pierre A, Corvol JC, Zelenika D, Lambert JC, Vidailhet M, Mellick GD, Lohmann E, Durif F, Pollak P, Damier P, Tison F, Silburn PA, Tzourio C, Forlani S, Loriot MA, Giroud M, Helmer C, Portet F, Amouyel P, Lathrop M, Elbaz A, Durr A, Martinez M, Brice A, French Parkinson's Disease Genetics Study G (2011) Genome-wide association study confirms BST1 and suggests a locus on 12q24 as the risk loci for Parkinson's disease in the European population. Hum Mol Genet 20:615-627. Santos D, Esteves AR, Silva DF, Januario C, Cardoso SM (2015) The Impact of Mitochondrial Fusion and Fission Modulation in Sporadic Parkinson's Disease. Mol Neurobiol 52:573-586. Satake W, Nakabayashi Y, Mizuta I, Hirota Y, Ito C, Kubo M, Kawaguchi T, Tsunoda T, Watanabe M, Takeda A, Tomiyama H, Nakashima K, Hasegawa K, Obata F, Yoshikawa T, Kawakami H, Sakoda S, Yamamoto M, Hattori N, Murata M, Nakamura Y, Toda T (2009) Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease. Nat Genet 41:1303-1307. Sharma M, Ioannidis JP, Aasly JO, Annesi G, Brice A, Van Broeckhoven C, Bertram L, Bozi M, Crosiers D, Clarke C, Facheris M, Farrer M, Garraux G, Gispert S, Auburger G, Vilarino-Guell C, Hadjigeorgiou GM, Hicks AA, Hattori N, Jeon B, Lesage S, Lill CM, Lin JJ, Lynch T, Lichtner P, Lang AE, Mok V, Jasinska-Myga B, Mellick GD, Morrison KE, Opala G, Pramstaller PP, Pichler I, Park SS, Quattrone A, Rogaeva E, Ross OA, Stefanis L, Stockton JD, Satake W, Silburn PA, Theuns J, Tan EK, Toda T, Tomiyama H, Uitti RJ, Wirdefeldt K, Wszolek Z, Xiromerisiou G, Yueh KC, Zhao Y, Gasser T, Maraganore D, Kruger R (2012) Large-scale replication and heterogeneity in Parkinson disease genetic loci. Neurology 79:659-667. Shavali S, Sens DA (2008) Synergistic neurotoxic effects of arsenic and dopamine in human dopaminergic neuroblastoma SH-SY5Y cells. Toxicological sciences : an official journal of the Society of Toxicology 102:254-261. Simon-Sanchez J, Marti-Masso JF, Sanchez-Mut JV, Paisan-Ruiz C, Martinez-Gil A, Ruiz-Martinez J, Saenz A, Singleton AB, Lopez de Munain A, Perez-Tur J (2006) Parkinson's disease due to the R1441G mutation in Dardarin: a founder effect in the Basques. Mov Disord 21:1954-1959. Simon-Sanchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, Berg D, Paisan-Ruiz C, Lichtner P, Scholz SW, Hernandez DG, Kruger R, Federoff M, Klein C, Goate A, Perlmutter J, Bonin M, Nalls MA, Illig T, Gieger C, Houlden H, Steffens M, Okun MS, Racette BA, Cookson MR, Foote KD, Fernandez HH, Traynor BJ, Schreiber S, Arepalli S, Zonozi R, Gwinn K, van der Brug M, Lopez G, Chanock SJ, Schatzkin A, Park Y, Hollenbeck A, Gao J, Huang X, Wood NW, Lorenz D, Deuschl G, Chen H, Riess O, Hardy JA, Singleton AB, Gasser T (2009) Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat Genet 41:1308-1312. Simon-Sanchez J, Singleton AB (2008) Sequencing analysis of OMI/HTRA2 shows previously reported pathogenic mutations in neurologically normal controls. Hum Mol Genet 17:1988-1993. Skibinski G, Nakamura K, Cookson MR, Finkbeiner S (2014) Mutant LRRK2 toxicity in neurons depends on LRRK2 levels and synuclein but not kinase activity or inclusion bodies. J Neurosci 34:418-433. Smargiassi A, Mutti A, De Rosa A, De Palma G, Negrotti A, Calzetti S (1998) A case-control study of occupational and environmental risk factors for Parkinson's disease in the Emilia-Romagna region of Italy. Neurotoxicology 19:709-712. Smith WW, Pei Z, Jiang H, Dawson VL, Dawson TM, Ross CA (2006) Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nat Neurosci 9:1231-1233. Spanaki C, Latsoudis H, Plaitakis A (2006) LRRK2 mutations on Crete: R1441H associated with PD evolving to PSP. Neurology 67:1518-1519. Stafa K, Trancikova A, Webber PJ, Glauser L, West AB, Moore DJ (2012) GTPase activity and neuronal toxicity of Parkinson's disease-associated LRRK2 is regulated by ArfGAP1. PLoS Genet 8:e1002526. Stafa K, Tsika E, Moser R, Musso A, Glauser L, Jones A, Biskup S, Xiong Y, Bandopadhyay R, Dawson VL, Dawson TM, Moore DJ (2014) Functional interaction of Parkinson's disease-associated LRRK2 with members of the dynamin | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77456 | - |
dc.description.abstract | 巴金森病是一個複雜性神經退化疾病,目前認為其病因可能由於基因與環境產生交互作用所引起的。最近相關研究顯示bone marrow stromal cell antigen 1 (BST1)、High temperature requirement A2(HTRA2)與Leucine-rich repeat kinase(LRRK2)基因突變或變異與巴金森病的發生有不同強度的相關性。
我們分析台灣巴金森病患者HTRA2的基因變異,結果共發現二個變異點(Pro143Ala與c.906 +3 G>A)。證明台灣巴金森病與HTRA2的基因變異有關。進一步建構GFP標記的cDNA質體,表現於初代多巴胺神經細胞,觀察發現Pro143Ala引起神經軸退化。人類神經瘤細胞株SH-SY5Y轉殖GFP標記的cDNA質體,經rotenone處理後,結果顯示相對於野生型SH-SY5Y細胞,Pro143Ala細胞可顯著觀察到粒腺體超顯微結構異常、粒腺體功能失調與細胞凋亡。此外,Pro143Ala增加HTRA2蛋白磷酸化表現,進而導致粒腺體功能失調。 根據最近全基因組關聯研究顯示BST1的單一核苷酸多型性rs11724635會提高罹患巴金森病的危險。因此我們探討在台灣巴金森病患者中BST1 rs11724635之基因流行病學研究研究中收集了468位巴金森病患者與487位健康對照組。結果顯示BST1 rs11724635表現頻率在病患組與健康組之間沒有顯者的差異,井水飲用在病患組與健康組之間有顯者的差異;然而國人若同時帶有BST1 rs11724635基因且曾飲用過井水則會明顯提高罹患巴金森病的危險。 LRRK2是最近被發現會導致偶發性與家族性巴金森病,LRRK2蛋白質包括armadillo (ARM)、ankyrin repeat (ANK)、leucine-rich repeat (LRR)、Ras of complex proteins: GTPase (ROC)、C-terminal of ROC (COR)、WD-40 (WD40)區塊。雖然目前對突變的LRRK2引起的致病機轉仍不明瞭,但已有許多研究發現LRRK2參與神經細胞的極性化、神經傳導物質、細胞膜與細胞骨架的動態平衡及蛋白質降解的調控。另外,亦有許多研究顯示細胞自噬可能為巴金森病的病理機轉之一。因此我們假設細胞自噬的機制可能參與LRRK2引起的巴金森病致病機轉。因此本實驗利用數種LRRK2基因轉殖鼠來探討此機制。結果發現hLRRK2 R1441G HET與HOM相對於同年齡的野生型老鼠皆有明顯地體重減輕、探究行為次數減少、步態異常與姿勢不穩。發現hLRRK2 R1441G HOM小鼠的GTase活性有增加之趨勢。另一方面,進一步穿透式電子顯微鏡與西方墨點法分析後發現12個月大的hLRRK2 R1441G HOM小鼠的黑質區發現溶體及粒腺體型態的改變且有自噬體的形成。因此,本實驗更加確認細胞自噬與GTase活性異常可能參與LRRK2 ROC區塊突變引起的巴金森病致病機轉。 | zh_TW |
dc.description.abstract | Parkinson‘s disease is a complex neurodegenerative disease, caused by a combination of various genetic and environmental factors. Recently, several studies indicates the bone marrow stromal cell antigen 1 (BST1), high temperature requirement A2 (HTRA2) and leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson’s disease (PD).
Mutations in HTRA2 re inconsistently associated with a risk of PD. We identified two novel heterozygous variants, Pro143Ala and c.906 +3 G>A. Expressing Pro143Ala variant of HTRA2 in primary dopaminergic neurons causes neurite degeneration. Following exposure to rotenone, the ultrastructural mitochondrial abnormality, the percentage of mitochondrial dysfunction and apoptosis in SH-SY5Y cells carrying the HTRA2 Pro143Ala a variant was significantly higher than wild-type cells. Mechanistically, protein level of phosphorylated HTRA2 was increased in cells carrying the Pro143Ala variant, suggesting Pro143Ala variant promotes HTRA2 phosphorylation with resultant mitochondrial dysfunction. Our results support a biologically relevant role of HTRA2 in PD susceptibility in Taiwanese. Further studies are warranted to confirm the role of HTRA2 Pro143Ala variant in the risk of PD. A recently published genome-wide association study in Caucasian and Asian populations showed a significant association between the BST1 SNP rs11724635 and increased risk for PD. We conduct a case control study to investigate whether BST1 rs11724635 increases the risk of PD, either by itself or in combination with environmental factors. 468 PD patients and 487 controls were evaluated. Compared with the AA genotype, the frequency of both CA and CC genotypes was not significantly different between the patient and control groups. The adjust odds ratios for CAand CC were 0.962 (95% CI = 0.643-1.439, p = 0.850) and 0.992 (95% CI = 0.654-1.503, p = 0.969) respectively. Of note, ever use of well water before the onset of PD symptoms had an impact on the occurrence of PD through interactions with BST1 rs11724635 AC and CC (OR = 1.623, p = 0.008). Our results show that the BST1 rs11724635 SNP alone is not associated with the development of PD, but it can interact with well water drinking to increase the risk of PD in this Taiwanese population. Mutations in LRRK2 are found in a significant proportion of sporadic and familial Parkinson’s disease (PD) patients. The LRRK2 protein contains multi-domains, including a GTPase and kinase domains. Although the mechanisms behind the pathogenic effects of LRRK2 mutations are still not clear, several in vitro and in vivo studies suggests roles in regulating neuronal polarity, neurotransmission, membrane and cytoskeletal dynamics and protein degradation. In addition, recent studies in the brains of PD patients and in animal models of PD indicate the emerging role of autophagy during PD pathogenesis. We hypothesized that autophagy potentiates associated LRRK2 pathophysiology. We used the transgenic mouse model overexpressing the human LRRK2 gene and R1441G heterozygous (R1441G HET) and homozygous (R1441G HOM) mutation in the human LRRK2 gene. We have performed a comprehensive analysis of these mice up to 12 months of age, including evaluation of body weight, behavioral testing, GTPase activity, TEM image and protein expression. Our results show that both of hLRRK2 R1441G HET and HOM mice reduce weight loss. Moreover, both of R1441G HET and HOM mice exhibit less exploratory rearing behavior compared with hLRRK2 mice at 9 and 12 months old. hLRRK2 R1441G HOM mice decreased the swing speed, stride length, and front paws of base of support comparing to hLRRK2 mice. In contrast, the stand, step cycle, duty cycle, and hind paws of base of support increased in hLRRK2 R1441G HOM mice. And hLRRK2R1441G HOM resulted in an increase in GTPase activity. As expected, lysosome and mitochondria defects and autophagosome were investigated in SN region of hLRRK2 R1441G HOM brain by transmission electron microscopy (TEM) at 12 months old. In addition, our also observed the impaired autophagy- related makers and mitochondria dynamic proteins by western blot. Finally, we confirm that mutation of LRRK2 ROC domain accompanied by autophagic and GTPase activity. | en |
dc.description.provenance | Made available in DSpace on 2021-07-10T22:02:50Z (GMT). No. of bitstreams: 1 ntu-107-D99b41008-1.pdf: 4316074 bytes, checksum: 14a91c92caeda8efd3db3036f08d481e (MD5) Previous issue date: 2018 | en |
dc.description.tableofcontents | 誌謝 I
中文摘要 II ABSTRACT IV CHAPTER 1. INTRODUCTION AND LITERATURE REVIEW 1 1.1. Parkinson’s disease 1 1.2. Disease Aetiology 1 1.2.1. Environmental factors 2 1.2.2. Genetics of PD 2 1.2.2.1. Genetic aspects of HTRA2-associated PD 3 1.2.2.2. Genetic aspects of LRRK2-associated PD 3 1.3. Genome-wide association studies in Parkinson's disease 5 1.3.1. Genetic aspects of BST1-associated PD 6 1.4. Hypothesis and thesis Aims 7 CHAPTER 2. NOVEL VARIANT Pro143Ala IN HTRA2 CONTRIBUTES TO PARKINSON'S DISEASE BY INDUCING HYPERPHOSPHORYLATION OF HTRA2 PROTEIN IN MITOCHONDRIA 8 2.1. Introduction 9 2.2. Materials and Methods 10 2.2.1. Subjects 10 2.2.2. HTRA2 screening in PD and control subjects 11 2.2.3. Relative quantification of HTRA2 gene expression in subjects with HTRA2 c.906 +3 G>A variation 11 2.2.4. In silico modeling of the crystal structure of HTRA2 with and without the c.427C>G (p.Pro143Ala) variation 12 2.2.5. Functional assay of HTRA2 c.427C>G (p.Pro143Ala) variation in vitro 13 2.2.5.1. Construction of HTRA2 expression plasmids and transfection in neuronal cells 13 2.2.5.2. Localization of HTRA2 protein and quantification of neurite outgrowth in primary dopaminergic neuron culture 14 2.2.5.3. Flow cytometric analysis of mitochondrial membrane potential and apoptosis induced by Rotenone 15 2.2.5.4. Transmission electron microscopy (TEM) imaging of mitochondrial morphology 15 2.2.5.5. Immunoprecipitation assay of phospho-HTRA2 protein 16 2.2.6. Statistical analysis 16 2.3. Results 16 2.4. Discussion 20 CHAPTER 3. BST1 rs11724635 INTERACTS WITH ENVIRONMENTAL FACTORS TO INCREASE THE RISK OF PARKINSON’S DISEASE IN A TAIWANESE POPULATION 24 3.1. Introduction 24 3.2. Materials and Methods 25 3.2.1. Study subjects 25 3.2.2. Genotyping 26 3.2.3. Questionnaire 26 3.2.4. Statistical analysis 27 3.3. Results 28 3.4. Discussion 29 CHAPTER 4. MUTATION OF LRRK2 ROC DOMAIN INDUCES MOTOR DYSFUNCTION, NEURONAL LOSS AND AUTOPHAGY IN A TRANSGENIC MICE MODEL 33 4.1. Introduction 33 4.1.1. LRRK2 gene structure and function 33 4.1.2. Role of the ROC domain in LRRK2 activity and function 34 4.1.3. LRRK2 and related signaling pathways 37 4.2. Materials and Methods 38 4.2.1. Mice 38 4.2.2. Genotype analysis by PCR 39 4.2.3. Body weight measurements 40 4.2.4. Behavioral Tests 40 4.2.4.1. Spontaneous locomotor activity 40 4.2.4.2. Spontaneous gait analysis 41 4.2.5. Guanosine triphosphatase (GTPase) assay 41 4.2.6. Transmission electron microscopy (TEM) 41 4.2.7. Fractionation of mitochondria 42 4.2.8. Tissue dissection 42 4.2.9. Protein extraction 42 4.2.10. Quantification of protein 43 4.2.11. SDS-PAGE 43 4.2.12. Western blot 44 4.2.13. Visualisation and data analysis 44 4.2.14. Statistical analysis 45 4.3. Results 45 4.3.1. Analyses of transgenic hLRRK2, hLRRK2R1441G+/- (HET) and hLRRK2R1441G+/+ (HOM) gene and protein expression 45 4.3.2. R1441G inhibited weight loss 45 4.3.3. Automated quantitative gait analysis. 46 4.3.4. Behavioral problems 46 4.3.5. LRRK2 R1441G HOM is positively associated to GTPase Activity 47 4.3.6. Mutant- hLRRK2 alters mitochondrial morphology in SNc region 47 4.3.7. R1441G increases mitochondrial recruitment of Drp1 and Fis 1 47 4.3.8. Investigation of the effects of hLRRK2 R1441G on the lysosome morphology in SNc region 48 4.3.9. Expression of autophagy in hLRRK2 R1441G HET and HOM mice in SNc region 48 4.4. Discussion 48 REFERENCES 55 TABLE AND FIGURE LISTS 80 APPENDIX 109 | |
dc.language.iso | en | |
dc.title | 巴金森氏症BST1、HTRA2及LRRK2基因變異的分子遺傳及功能研究 | zh_TW |
dc.title | Molecular Genetic and Functional Studies of BST1, HTRA2 and LRRK2 Gene Variations in Parkinson's Disease | en |
dc.type | Thesis | |
dc.date.schoolyear | 107-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 李桂楨(Guey-Jen Lee-Chen),王致恬(Chih-Tien Wang),朱家瑩(Chia-Ying Chu),林靜嫻(Chin-Hsien Lin) | |
dc.subject.keyword | 巴金森病,BST1,HTRA2,LRRK2,環境因子,粒腺體,自噬體, | zh_TW |
dc.subject.keyword | Parkinson’s disease,BST1,HTRA2,LRRK2,environmental factor,mitochondria,autophagosome, | en |
dc.relation.page | 124 | |
dc.identifier.doi | 10.6342/NTU201803986 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2018-09-13 | |
dc.contributor.author-college | 生命科學院 | zh_TW |
dc.contributor.author-dept | 生命科學系 | zh_TW |
顯示於系所單位: | 生命科學系 |
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