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Genetika a fenotypová charakteristika Parkinsonovy nemoci s časným začátkem
Název práce v češtině: Genetika a fenotypová charakteristika Parkinsonovy nemoci s časným začátkem
Název v anglickém jazyce: Genetics and phenotypic characteristics of early-onset Parkinson’s disease
Klíčová slova: alelické varianty, fenotyp, genotyp, mutace, PARK2, parkin, Parkinsonova nemoc s časným začátkem, polymorfismy
Klíčová slova anglicky: allelic variants, early-onset Parkinson's disease, genotype, mutations, PARK2, parkin, phenotype, polymorphisms
Akademický rok vypsání: 2013/2014
Typ práce: disertační práce
Jazyk práce: čeština
Ústav: Neurologická klinika 1. LF UK a VFN (11-00600)
Vedoucí / školitel: prof. MUDr. Evžen Růžička, DrSc.
Řešitel: skrytý - zadáno a potvrzeno stud. odd.
Datum přihlášení: 12.06.2014
Datum zadání: 12.06.2014
Datum potvrzení stud. oddělením: 12.06.2014
Datum a čas obhajoby: 29.09.2014 15:15
Místo konání obhajoby: Neurologická klinika 1. LF UK a VFN
Datum odevzdání elektronické podoby:20.06.2014
Datum proběhlé obhajoby: 29.09.2014
Předmět: Obhajoba dizertační práce (B90002)
Oponenti: prof. MUDr. Pavel Seeman, Ph.D.
  prof. MUDr. Martin Bojar, CSc.
 
 
Seznam odborné literatury
[1] Ahle S, Ungewickell E. Auxilin, a newly identified clathrin-associated protein in coated vesicles from bovine brain. J Cell Biol 1990; 111 (1): 19-29.
[2] Ahlskog JE. Parkin and PINK1 parkinsonism may represent nigral mitochondrial cytopathies distinct from Lewy body Parkinson's disease. Parkinsonism Relat Disord 2009; 15 (10): 721-727.
[3] Alcalay RN, Siderowf A, Ottman R, Caccappolo E, Mejia-Santana H, Tang MX et al. Olfaction in Parkin heterozygotes and compound heterozygotes: the CORE-PD study. Neurology 2011; 76 (4): 319-326.
[4] Anderson PC, Daggett V. Molecular basis for the structural instability of human DJ-1 induced by the L166P mutation associated with Parkinson's disease. Biochemistry 2008; 47 (36): 9380-9393.
[5] Appel-Cresswell S, Vilarino-Guell C, Encarnacion M, Sherman H, Yu I, Shah B et al. Alpha-synuclein p.H50Q, a novel pathogenic mutation for Parkinson's disease. Mov Disord 2013; 28 (6): 811-813.
[6] Autere J, Moilanen JS, Finnila S, Soininen H, Mannermaa A, Hartikainen P et al. Mitochondrial DNA polymorphisms as risk factors for Parkinson's disease and Parkinson's disease dementia. Hum Genet 2004; 115 (1): 29-35.
[7] Avraham E, Rott R, Liani E, Szargel R, Engelender S. Phosphorylation of Parkin by the Cyclin-dependent Kinase 5 at the Linker Region Modulates Its Ubiquitin-Ligase Activity and Aggregation. J Biol Chem 2007; 282 (17): 12842-12850.
[8] Balsinde J, Balboa MA. Cellular regulation and proposed biological functions of group VIA calcium-independent phospholipase A2 in activated cells. Cell Signal 2005; 17 (9): 1052-1062.
[9] Bembi B, Zambito Marsala S, Sidransky E, Ciana G, Carrozzi M, Zorzon M et al. Gaucher's disease with Parkinson's disease: clinical and pathological aspects. Neurology 2003; 61 (1): 99-101.
[10] Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK, Perry RH et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet 2006; 38 (5): 515-517.
[11] Bennett MC. The role of alpha-synuclein in neurodegenerative diseases. Pharmacol Ther 2005; 105 (3): 311-331.
[12] Bodner RA, Outeiro TF, Altmann S, Maxwell MM, Cho SH, Hyman BT et al. Pharmacological promotion of inclusion formation: A therapeutic approach for Huntington's and Parkinson's diseases. PNAS 2006; 103 (11): 4246-4251.
[13] Bonifati V. Genetics of Parkinson's disease--state of the art, 2013. Parkinsonism Relat Disord 2014; 20 Suppl 1 S23-28.
[14] Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E et al. Mutations in the DJ-1 Gene Associated with Autosomal Recessive Early-Onset Parkinsonism. Science 2003; 299 (5604): 256-259.
[15] Bower JH, Maraganore DM, McDonnell SK, Rocca WA. Incidence and distribution of parkinsonism in Olmsted County, Minnesota, 1976-1990. Neurology 1999; 52 (6): 1214-1220.
[16] Bozi M, Papadimitriou D, Antonellou R, Moraitou M, Maniati M, Vassilatis DK et al. Genetic assessment of familial and early-onset Parkinson's disease in a Greek population. Eur J Neurol 2013;
[17] Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 2003; 24 (2): 197-211.
[18] Braak H, Rub U, Jansen Steur EN, Del Tredici K, de Vos RA. Cognitive status correlates with neuropathologic stage in Parkinson disease. Neurology 2005; 64 (8): 1404-1410.
[19] Bronstein JM, Tagliati M, Alterman RL, Lozano AM, Volkmann J, Stefani A et al. Deep brain stimulation for Parkinson disease: an expert consensus and review of key issues. Arch Neurol 2011; 68 (2): 165.
[20] Brooks J, Ding J, Simon-Sanchez J, Paisan-Ruiz C, Singleton AB, Scholz SW. Parkin and PINK1 mutations in early-onset Parkinson's disease: comprehensive screening in publicly available cases and control. J Med Genet 2009; 46 (6): 375-381.
[21] Bruggemann N, Klein C. Parkin Type of Early-Onset Parkinson Disease. 1993;
[22] Buhmann C, Binkofski F, Klein C, Buchel C, van Eimeren T, Erdmann C et al. Motor reorganization in asymptomatic carriers of a single mutant Parkin allele: a human model for presymptomatic parkinsonism. Brain 2005; 128 (10): 2281-2290.
[23] Burchell VS, Nelson DE, Sanchez-Martinez A, Delgado-Camprubi M, Ivatt RM, Pogson JH et al. The Parkinson's disease-linked proteins Fbxo7 and Parkin interact to mediate mitophagy. Nat Neurosci 2013; 16 (9): 1257-1265.
[24] Carmine Belin A, Westerlund M, Bergman O, Nissbrandt H, Lind C, Sydow O et al. S18Y in ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) associated with decreased risk of Parkinson's disease in Sweden. Parkinsonism Relat Disord 2007; 13 (5): 295-298.
[25] Clark LN, Wang Y, Karlins E, Saito L, Mejia-Santana H, Harris J et al. Frequency of LRRK2 mutations in early- and late-onset Parkinson disease. Neurology 2006; 67 (10): 1786-1791.
[26] Clayton DF, George JM. Synucleins in synaptic plasticity and neurodegenerative disorders. J Neurosci Res 1999; 58 (1): 120-129.
[27] Clements CM, McNally RS, Conti BJ, Mak TW, Ting JPY. DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. PNAS 2006; 103 (41): 15091-15096.
[28] Cookson MR. The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease. Nat Rev Neurosci 2010; 11 (12): 791-797.
[29] Cookson MR, Lockhart PJ, McLendon C, O'Farrell C, Schlossmacher M, Farrer MJ. RING finger 1 mutations in Parkin produce altered localization of the protein. Hum Mol Genet 2003; 12 (22): 2957-2965.
[30] Corti O, Lesage S, Brice A. What genetics tells us about the causes and mechanisms of Parkinson's disease. Physiol Rev 2011; 91 (4): 1161-1218.
[31] Cremona O, Di Paolo G, Wenk MR, Luthi A, Kim WT, Takei K et al. Essential role of phosphoinositide metabolism in synaptic vesicle recycling. Cell 1999; 99 (2): 179-188.
[32] de Lau LM, Breteler MM. Epidemiology of Parkinson's disease. Lancet Neurol 2006; 5 (6): 525-535.
[33] de Mena L, Samaranch LL, Coto E, Cardo LF, Ribacoba R, Lorenzo-Betancor O et al. Mutational screening of PARKIN identified a 3' UTR variant (rs62637702) associated with Parkinson's disease. J Mol Neurosci 2013; 50 (2): 264-269.
[34] Dehay B, Martinez-Vicente M, Caldwell GA, Caldwell KA, Yue Z, Cookson MR et al. Lysosomal impairment in Parkinson's disease. Mov Disord 2013; 28 (6): 725-732.
[35] Dekker MC, Eshuis SA, Maguire RP, Veenma-van der Du L, Pruim J, Snijders PJ et al. PET neuroimaging and mutations in the DJ-1 gene. J Neural Transm 2004; 111 (12): 1575-1581.
[36] Deleidi M, Gasser T. The role of inflammation in sporadic and familial Parkinson's disease. Cell Mol Life Sci 2013; 70 (22): 4259-4273.
[37] Deng H, Gao K, Jankovic J. The VPS35 gene and Parkinson's disease. Mov Disord 2013a; 28 (5): 569-575.
[38] Deng H, Liang H, Jankovic J. F-box only protein 7 gene in parkinsonian-pyramidal disease. JAMA Neurol 2013b; 70 (1): 20-24.
[39] Deng J, Lewis PA, Greggio E, Sluch E, Beilina A, Cookson MR. Structure of the ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase. Proc Natl Acad Sci U S A 2008; 105 (5): 1499-1504.
[40] Devine MJ, Plun-Favreau H, Wood NW. Parkinson's disease and cancer: two wars, one front. Nat Rev Cancer 2011; 11 (11): 812-823.
[41] Di Fonzo A, Dekker MC, Montagna P, Baruzzi A, Yonova EH, Correia Guedes L et al. FBXO7 mutations cause autosomal recessive, early-onset parkinsonian-pyramidal syndrome. Neurology 2009; 72 (3): 240-245.
[42] Di Fonzo A, Chien HF, Socal M, Giraudo S, Tassorelli C, Iliceto G et al. ATP13A2 missense mutations in juvenile parkinsonism and young onset Parkinson disease. Neurology 2007; 68 (19): 1557-1562.
[43] Do CB, Tung JY, Dorfman E, Kiefer AK, Drabant EM, Francke U et al. Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson's disease. PLoS Genet 2011; 7 (6): e1002141.
[44] Doherty KM, Silveira-Moriyama L, Parkkinen L, Healy DG, Farrell M, Mencacci NE et al. Parkin disease: a clinicopathologic entity? JAMA Neurol 2013; 70 (5): 571-579.
[45] Douglas PM, Dillin A. Protein homeostasis and aging in neurodegeneration. J Cell Biol 2010; 190 (5): 719-729.
[46] Edvardson S, Cinnamon Y, Ta-Shma A, Shaag A, Yim YI, Zenvirt S et al. A deleterious mutation in DNAJC6 encoding the neuronal-specific clathrin-uncoating co-chaperone auxilin, is associated with juvenile parkinsonism. PLoS ONE 2012; 7 (5): e36458.
[47] Esposito G, Ana Clara F, Verstreken P. Synaptic vesicle trafficking and Parkinson's disease. Dev Neurobiol 2012; 72 (1): 134-144.
[48] Exner N, Lutz AK, Haass C, Winklhofer KF. Mitochondrial dysfunction in Parkinson's disease: molecular mechanisms and pathophysiological consequences. EMBO J 2012; 31 (14): 3038-3062.
[49] Farrer MJ, Stone JT, Lin CH, Dachsel JC, Hulihan MM, Haugarvoll K et al. Lrrk2 G2385R is an ancestral risk factor for Parkinson's disease in Asia. Parkinsonism Relat Disord 2007; 13 (2): 89-92.
[50] Fiala O, Ruzicka E. Mezinárodní databáze Touretteova syndromu: zapojení do projektu v České republice. Cesk Slov Neurol N 2003; 33/99 (3): 197-202.
[51] Follett J, Norwood SJ, Hamilton NA, Mohan M, Kovtun O, Tay S et al. The Vps35 D620N mutation linked to Parkinson's disease disrupts the cargo sorting function of retromer. Traffic 2014; 15 (2): 230-244.
[52] Funayama M, Hasegawa K, Kowa H, Saito M, Tsuji S, Obata F. A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2-q13.1. Ann Neurol 2002; 51 (3): 296-301.
[53] Gallus S, Lugo A, La Vecchia C, Boffetta P, Chaloupka FJ, Colombo P et al. Pricing Policies And Control of Tobacco in Europe (PPACTE) project: cross-national comparison of smoking prevalence in 18 European countries. Eur J Cancer Prev 2014; 23 (3): 177-185.
[54] Gasser T, Muller-Myhsok B, Wszolek ZK, Oehlmann R, Calne DB, Bonifati V et al. A susceptibility locus for Parkinson's disease maps to chromosome 2p13. Nat Genet 1998; 18 (3): 262-265.
[55] Gaweda-Walerych K, Safranow K, Jasinska-Myga B, Bialecka M, Klodowska-Duda G, Rudzinska M et al. PARK2 variability in Polish Parkinson's disease patients--interaction with mitochondrial haplogroups. Parkinsonism Relat Disord 2012; 18 (5): 520-524.
[56] Gegg ME, Burke D, Heales SJ, Cooper JM, Hardy J, Wood NW et al. Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains. Ann Neurol 2012; 72 (3): 455-463.
[57] Gegg ME, Cooper JM, Chau KY, Rojo M, Schapira AH, Taanman JW. Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy. Hum Mol Genet 2010; 19 (24): 4861-4870.
[58] Geisler S, Holmstrom KM, Skujat D, Fiesel FC, Rothfuss OC, Kahle PJ et al. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol 2010; 12 (2): 119-131.
[59] Gelmetti V, Ferraris A, Brusa L, Romano F, Lombardi F, Barzaghi C et al. Late onset sporadic Parkinson's disease caused by PINK1 mutations: clinical and functional study. Mov Disord 2008; 23 (6): 881-885.
[60] Giovannini P, Piccolo I, Genitrini S, Soliveri P, Girotti F, Geminiani G et al. Early-onset Parkinson's disease. Mov Disord 1991; 6 (1): 36-42.
[61] Glauser L, Sonnay S, Stafa K, Moore DJ. Parkin promotes the ubiquitination and degradation of the mitochondrial fusion factor mitofusin 1. J Neurochem 2011; 118 (4): 636-645.
[62] Goldberg MS, Lansbury PT, Jr. Is there a cause-and-effect relationship between alpha-synuclein fibrillization and Parkinson's disease? Nat Cell Biol 2000; 2 (7): E115-119.
[63] Gorner K, Holtorf E, Waak J, Pham T-T, Vogt-Weisenhorn DM, Wurst W et al. Structural Determinants of the C-terminal Helix-Kink-Helix Motif Essential for Protein Stability and Survival Promoting Activity of DJ-1. J Biol Chem 2007; 282 (18): 13680-13691.
[64] Gowers W (1900) A Manual of Diseases of the Nervous System, Vol. 1, Philadelphia: Blakiston's Son.
[65] Greenbaum EA, Graves CL, Mishizen-Eberz AJ, Lupoli MA, Lynch DR, Englander SW et al. The E46K mutation in alpha-synuclein increases amyloid fibril formation. J Biol Chem 2005; 280 (9): 7800-7807.
[66] Grunewald A, Arns B, Seibler P, Rakovic A, Munchau A, Ramirez A et al. ATP13A2 mutations impair mitochondrial function in fibroblasts from patients with Kufor-Rakeb syndrome. Neurobiol Aging 2012; 33 (8): 1843 e1841-1847.
[67] Grunewald A, Kasten M, Ziegler A, Klein C. Next-generation phenotyping using the parkin example: time to catch up with genetics. JAMA Neurol 2013; 70 (9): 1186-1191.
[68] Guerrero Camacho JL, Monroy Jaramillo N, Yescas Gomez P, Rodriguez Violante M, Boll Woehrlen C, Alonso Vilatela ME et al. High frequency of Parkin exon rearrangements in Mexican-mestizo patients with early-onset Parkinson's disease. Mov Disord 2012; 27 (8): 1047-1051.
[69] Gui YX, Xu ZP, Wen L, Liu HM, Zhao JJ, Hu XY. Four novel rare mutations of PLA2G6 in Chinese population with Parkinson's disease. Parkinsonism Relat Disord 2013; 19 (1): 21-26.
[70] Habig K, Walter M, Poths S, Riess O, Bonin M. RNA interference of LRRK2-microarray expression analysis of a Parkinson's disease key player. Neurogenetics 2008; 9 (2): 83-94.
[71] Haehner A, Boesveldt S, Berendse HW, Mackay-Sim A, Fleischmann J, Silburn PA et al. Prevalence of smell loss in Parkinson's disease--a multicenter study. Parkinsonism Relat Disord 2009; 15 (7): 490-494.
[72] Hagenah JM, Konig IR, Becker B, Hilker R, Kasten M, Hedrich K et al. Substantia nigra hyperechogenicity correlates with clinical status and number of Parkin mutated alleles. J Neurol 2007; 254 (10): 1407-1413.
[73] Halliday GM, Stevens CH. Glia: initiators and progressors of pathology in Parkinson's disease. Mov Disord 2011; 26 (1): 6-17.
[74] Hampe C, Ardila-Osorio H, Fournier M, Brice A, Corti O. Biochemical analysis of Parkinson's disease-causing variants of Parkin, an E3 ubiquitin-protein ligase with monoubiquitylation capacity. Hum Mol Genet 2006; 15 (13): 2059-2075.
[75] Hampshire DJ, Roberts E, Crow Y, Bond J, Mubaidin A, Wriekat AL et al. Kufor-Rakeb syndrome, pallido-pyramidal degeneration with supranuclear upgaze paresis and dementia, maps to 1p36. J Med Genet 2001; 38 (10): 680-682.
[76] Happe S, Berger K. The association of dopamine agonists with daytime sleepiness, sleep problems and quality of life in patients with Parkinson's disease--a prospective study. J Neurol 2001; 248 (12): 1062-1067.
[77] Healy DG, Falchi M, O'Sullivan SS, Bonifati V, Durr A, Bressman S et al. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurol 2008; 7 (7): 583-590.
[78] Hedrich K, Djarmati A, Schafer N, Hering R, Wellenbrock C, Weiss PH et al. DJ-1 (PARK7) mutations are less frequent than Parkin (PARK2) mutations in early-onset Parkinson disease. Neurology 2004; 62 (3): 389-394.
[79] Hedrich K, Winkler S, Hagenah J, Kabakci K, Kasten M, Schwinger E et al. Recurrent LRRK2 (Park8) mutations in early-onset Parkinson's disease. Mov Disord 2006; 21 (9): 1506-1510.
[80] Henn IH, Bouman L, Schlehe JS, Schlierf A, Schramm JE, Wegener E et al. Parkin Mediates Neuroprotection through Activation of I{kappa}B Kinase/Nuclear Factor-{kappa}B Signaling. J Neurosci 2007; 27 (8): 1868-1878.
[81] Herrup K, Yang Y. Cell cycle regulation in the postmitotic neuron: oxymoron or new biology? Nat Rev Neurosci 2007; 8 (5): 368-378.
[82] Hicks AA, Petursson H, Jonsson T, Stefansson H, Johannsdottir HS, Sainz J et al. A susceptibility gene for late-onset idiopathic Parkinson's disease. Ann Neurol 2002; 52 (5): 549-555.
[83] Hilker R, Klein C, Ghaemi M, Kis B, Strotmann T, Ozelius LJ et al. Positron emission tomographic analysis of the nigrostriatal dopaminergic system in familial parkinsonism associated with mutations in the parkin gene. Ann Neurol 2001; 49 (3): 367-376.
[84] Hirst J, Sahlender DA, Li S, Lubben NB, Borner GH, Robinson MS. Auxilin depletion causes self-assembly of clathrin into membraneless cages in vivo. Traffic 2008; 9 (8): 1354-1371.
[85] Horvath R, Kley RA, Lochmuller H, Vorgerd M. Parkinson syndrome, neuropathy, and myopathy caused by the mutation A8344G (MERRF) in tRNALys. Neurology 2007; 68 (1): 56-58.
[86] Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992; 55 (3): 181-184.
[87] Chang XL, Mao XY, Li HH, Zhang JH, Li NN, Burgunder JM et al. Functional parkin promoter polymorphism in Parkinson's disease: new data and meta-analysis. J Neurol Sci 2011; 302 (1-2): 68-71.
[88] Chang YF, Cheng CM, Chang LK, Jong YJ, Yuo CY. The F-box protein Fbxo7 interacts with human inhibitor of apoptosis protein cIAP1 and promotes cIAP1 ubiquitination. Biochem Biophys Res Commun 2006; 342 (4): 1022-1026.
[89] Chartier-Harlin MC, Dachsel JC, Vilarino-Guell C, Lincoln SJ, Lepretre F, Hulihan MM et al. Translation initiator EIF4G1 mutations in familial Parkinson disease. Am J Hum Genet 2011; 89 (3): 398-406.
[90] Chaugule VK, Burchell L, Barber KR, Sidhu A, Leslie SJ, Shaw GS et al. Autoregulation of Parkin activity through its ubiquitin-like domain. EMBO J 2011; 30 (14): 2853-2867.
[91] Cherra SJ, 3rd, Steer E, Gusdon AM, Kiselyov K, Chu CT. Mutant LRRK2 elicits calcium imbalance and depletion of dendritic mitochondria in neurons. Am J Pathol 2013; 182 (2): 474-484.
[92] Choi JM, Woo MS, Ma HI, Kang SY, Sung YH, Yong SW et al. Analysis of PARK genes in a Korean cohort of early-onset Parkinson disease. Neurogenetics 2008; 9 (4): 263-269.
[93] Chung KK, Zhang Y, Lim KL, Tanaka Y, Huang H, Gao J et al. Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease. Nat Med 2001; 7 (10): 1144-1150.
[94] Iaccarino C, Crosio C, Vitale C, Sanna G, Carri MT, Barone P. Apoptotic mechanisms in mutant LRRK2-mediated cell death. Hum Mol Genet 2007; 16 (11): 1319-1326.
[95] Ibanez P, Bonnet AM, Debarges B, Lohmann E, Tison F, Pollak P et al. Causal relation between alpha-synuclein gene duplication and familial Parkinson's disease. Lancet 2004; 364 (9440): 1169-1171.
[96] Imai Y, Soda M, Inoue H, Hattori N, Mizuno Y, Takahashi R. An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 2001; 105 (7): 891-902.
[97] Ishihara-Paul L, Hulihan MM, Kachergus J, Upmanyu R, Warren L, Amouri R et al. PINK1 mutations and parkinsonism. Neurology 2008; 71 (12): 896-902.
[98] Jankovic J. Parkinson's disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 2008; 79 (4): 368-376.
[99] Junn E, Ronchetti RD, Quezado MM, Kim SY, Mouradian MM. Tissue transglutaminase-induced aggregation of alpha-synuclein: Implications for Lewy body formation in Parkinson's disease and dementia with Lewy bodies. Proc Natl Acad Sci U S A 2003; 100 (4): 2047-2052.
[100] Junn E, Taniguchi H, Jeong BS, Zhao X, Ichijo H, Mouradian MM. Interaction of DJ-1 with Daxx inhibits apoptosis signal-regulating kinase 1 activity and cell death. PNAS 2005; 102 (27): 9691-9696.
[101] Kachergus J, Mata IF, Hulihan M, Taylor JP, Lincoln S, Aasly J et al. Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. Am J Hum Genet 2005; 76 (4): 672-680.
[102] Kalia LV, Kalia SK, McLean PJ, Lozano AM, Lang AE. alpha-Synuclein oligomers and clinical implications for Parkinson disease. Ann Neurol 2013; 73 (2): 155-169.
[103] Kann M, Jacobs H, Mohrmann K, Schumacher K, Hedrich K, Garrels J et al. Role of parkin mutations in 111 community-based patients with early-onset parkinsonism. Ann Neurol 2002; 51 (5): 621-625.
[104] Kasten M, Klein C. The many faces of alpha-synuclein mutations. Mov Disord 2013; 28 (6): 697-701.
[105] Kawahara K, Hashimoto M, Bar-On P, Ho GJ, Crews L, Mizuno H et al. {alpha}-Synuclein Aggregates Interfere with Parkin Solubility and Distribution: ROLE IN THE PATHOGENESIS OF PARKINSON DISEASE. J Biol Chem 2008; 283 (11): 6979-6987.
[106] Kay DM, Moran D, Moses L, Poorkaj P, Zabetian CP, Nutt J et al. Heterozygous parkin point mutations are as common in control subjects as in Parkinson's patients. Ann Neurol 2007; 61 (1): 47-54.
[107] Keller MF, Saad M, Bras J, Bettella F, Nicolaou N, Simon-Sanchez J et al. Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease. Hum Mol Genet 2012; 21 (22): 4996-5009.
[108] Kett LR, Boassa D, Ho CC, Rideout HJ, Hu J, Terada M et al. LRRK2 Parkinson disease mutations enhance its microtubule association. Hum Mol Genet 2012; 21 (4): 890-899.
[109] Khan NL, Brooks DJ, Pavese N, Sweeney MG, Wood NW, Lees AJ et al. Progression of nigrostriatal dysfunction in a parkin kindred: an [18F]dopa PET and clinical study. Brain 2002a; 125 (10): 2248-2256.
[110] Khan NL, Graham E, Critchley P, Schrag AE, Wood NW, Lees AJ et al. Parkin disease: a phenotypic study of a large case series. Brain 2003; 126 (Pt 6): 1279-1292.
[111] Khan NL, Katzenschlager R, Watt H, Bhatia KP, Wood NW, Quinn N et al. Olfaction differentiates parkin disease from early-onset parkinsonism and Parkinson disease. Neurology 2004; 62 (7): 1224-1226.
[112] Khan NL, Valente EM, Bentivoglio AR, Wood NW, Albanese A, Brooks DJ et al. Clinical and subclinical dopaminergic dysfunction in PARK6-linked parkinsonism: an 18F-dopa PET study. Ann Neurol 2002b; 52 (6): 849-853.
[113] Khateeb S, Flusser H, Ofir R, Shelef I, Narkis G, Vardi G et al. PLA2G6 mutation underlies infantile neuroaxonal dystrophy. Am J Hum Genet 2006; 79 (5): 942-948.
[114] Kieburtz K, Wunderle KB. Parkinson's disease: evidence for environmental risk factors. Mov Disord 2013; 28 (1): 8-13.
[115] Kiely AP, Asi YT, Kara E, Limousin P, Ling H, Lewis P et al. alpha-Synucleinopathy associated with G51D SNCA mutation: a link between Parkinson's disease and multiple system atrophy? Acta Neuropathol 2013; 125 (5): 753-769.
[116] Kilarski LL, Pearson JP, Newsway V, Majounie E, Knipe MD, Misbahuddin A et al. Systematic review and UK-based study of PARK2 (parkin), PINK1, PARK7 (DJ-1) and LRRK2 in early-onset Parkinson's disease. Mov Disord 2012; 27 (12): 1522-1529.
[117] Kim HJ, Lee JY, Yun JY, Kim SY, Park SS, Jeon BS. Phenotype analysis in patients with early onset Parkinson's disease with and without parkin mutations. J Neurol 2011; 258 (12): 2260-2267.
[118] Kinumi T, Kimata J, Taira T, Ariga H, Niki E. Cysteine-106 of DJ-1 is the most sensitive cysteine residue to hydrogen peroxide-mediated oxidation in vivo in human umbilical vein endothelial cells. Biochem Biophys Res Commun 2004; 317 (3): 722-728.
[119] Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 1998; 392 (6676): 605-608.
[120] Kitao Y, Imai Y, Ozawa K, Kataoka A, Ikeda T, Soda M et al. Pael receptor induces death of dopaminergic neurons in the substantia nigra via endoplasmic reticulum stress and dopamine toxicity, which is enhanced under condition of parkin inactivation. Hum Mol Genet 2007; 16 (1): 50-60.
[121] Klein C. Implications of genetics on the diagnosis and care of patients with Parkinson disease. Arch Neurol 2006; 63 (3): 328-334.
[122] Klein C, Lohmann-Hedrich K, Rogaeva E, Schlossmacher MG, Lang AE. Deciphering the role of heterozygous mutations in genes associated with parkinsonism. Lancet Neurol 2007; 6 (7): 652-662.
[123] Klein C, Westenberger A. Genetics of Parkinson's disease. Cold Spring Harb Perspect Med 2012; 2 (1): a008888.
[124] Ko HS, von Coelln R, Sriram SR, Kim SW, Chung KKK, Pletnikova O et al. Accumulation of the Authentic Parkin Substrate Aminoacyl-tRNA Synthetase Cofactor, p38/JTV-1, Leads to Catecholaminergic Cell Death. J Neurosci 2005; 25 (35): 7968-7978.
[125] Koroglu C, Baysal L, Cetinkaya M, Karasoy H, Tolun A. DNAJC6 is responsible for juvenile parkinsonism with phenotypic variability. Parkinsonism Relat Disord 2013; 19 (3): 320-324.
[126] Kostic VS, Filipovic SR, Lecic D, Momcilovic D, Sokic D, Sternic N. Effect of age at onset on frequency of depression in Parkinson's disease. J Neurol Neurosurg Psychiatry 1994; 57 (10): 1265-1267.
[127] Koziorowski D, Hoffman-Zacharska D, Slawek J, Szirkowiec W, Janik P, Bal J et al. Low frequency of the PARK2 gene mutations in Polish patients with the early-onset form of Parkinson disease. Parkinsonism Relat Disord 2010; 16 (2): 136-138.
[128] Kraytsberg Y, Kudryavtseva E, McKee AC, Geula C, Kowall NW, Khrapko K. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat Genet 2006; 38 (5): 518-520.
[129] Krebs CE, Karkheiran S, Powell JC, Cao M, Makarov V, Darvish H et al. The Sac1 domain of SYNJ1 identified mutated in a family with early-onset progressive Parkinsonism with generalized seizures. Hum Mutat 2013; 34 (9): 1200-1207.
[130] Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S et al. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nat Genet 1998; 18 (2): 106-108.
[131] Kruger R, Sharma M, Riess O, Gasser T, Van Broeckhoven C, Theuns J et al. A large-scale genetic association study to evaluate the contribution of Omi/HtrA2 (PARK13) to Parkinson's disease. Neurobiol Aging 2011; 32 (3): 548 e549-518.
[132] Kubo SI, Kitami T, Noda S, Shimura H, Uchiyama Y, Asakawa S et al. Parkin is associated with cellular vesicles. J Neurochem 2001; 78 (1): 42-54.
[133] Kuroda Y, Mitsui T, Kunishige M, Shono M, Akaike M, Azuma H et al. Parkin enhances mitochondrial biogenesis in proliferating cells. Hum Mol Genet 2006; 15 (6): 883-895.
[134] Kyratzi E, Pavlaki M, Stefanis L. The S18Y polymorphic variant of UCH-L1 confers an antioxidant function to neuronal cells. Hum Mol Genet 2008; ddn115.
[135] Laitinen J, Samarut J, Holtta E. A nontoxic and versatile protein salting-out method for isolation of DNA. Biotechniques 1994; 17 (2): 316, 318, 320-312.
[136] Laman H. Fbxo7 gets proactive with cyclin D/cdk6. Cell Cycle 2006; 5 (3): 279-282.
[137] Lautier C, Goldwurm S, Durr A, Giovannone B, Tsiaras WG, Pezzoli G et al. Mutations in the GIGYF2 (TNRC15) gene at the PARK11 locus in familial Parkinson disease. Am J Hum Genet 2008; 82 (4): 822-833.
[138] Lee SJ. Origins and effects of extracellular alpha-synuclein: implications in Parkinson's disease. J Mol Neurosci 2008; 34 (1): 17-22.
[139] Lee WW, Jeon BS. Clinical spectrum of dopa-responsive dystonia and related disorders. Curr Neurol Neurosci Rep 2014; 14 (7): 461.
[140] Leroux P (1890) Contribution à l'étude des causes de la paralysie agitante. in Thesis, Paris.
[141] Leroy E, Boyer R, Auburger G, Leube B, Ulm G, Mezey E et al. The ubiquitin pathway in Parkinson's disease. Nature 1998; 395 (6701): 451-452.
[142] Lesage S, Brice A. Parkinson's disease: from monogenic forms to genetic susceptibility factors. Hum Mol Genet 2009; 18 (R1): R48-59.
[143] Lesage S, Condroyer C, Lohman E, Troiano A, Tison F, Viallet F et al. Follow-up study of the GIGYF2 gene in French families with Parkinson's disease. Neurobiol Aging 2010; 31 (6): 1069-1071; discussion 1072-1064.
[144] Lesage S, Durr A, Tazir M, Lohmann E, Leutenegger A-L, Janin S et al. LRRK2 G2019S as a Cause of Parkinson's Disease in North African Arabs. N Engl J Med 2006; 354 (4): 422-423.
[145] Lev N, Ickowicz D, Melamed E, Offen D. Oxidative insults induce DJ-1 upregulation and redistribution: Implications for neuroprotection. Neurotoxicology 2008; 29 (3): 397-405.
[146] Li JY, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ et al. Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nat Med 2008; 14 (5): 501-503.
[147] Li L, Funayama M, Tomiyama H, Li Y, Yoshino H, Sasaki R et al. No evidence for pathogenic role of GIGYF2 mutation in Parkinson disease in Japanese patients. Neurosci Lett 2010;
[148] Lichtenberg M, Mansilla A, Zecchini VR, Fleming A, Rubinsztein DC. The Parkinson's disease protein LRRK2 impairs proteasome substrate clearance without affecting proteasome catalytic activity. Cell Death Dis 2011; 2 e196.
[149] Liu Y, Fallon L, Lashuel HA, Liu Z, Lansbury PT. The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility. Cell 2002; 111 (2): 209-218.
[150] Lohmann E, Periquet M, Bonifati V, Wood NW, De Michele G, Bonnet AM et al. How much phenotypic variation can be attributed to parkin genotype? Ann Neurol 2003; 54 (2): 176-185.
[151] Lohmann E, Thobois S, Lesage S, Broussolle E, du Montcel ST, Ribeiro MJ et al. A multidisciplinary study of patients with early-onset PD with and without parkin mutations. Neurology 2009; 72 (2): 110-116.
[152] Lopez de Maturana R, Aguila JC, Sousa A, Vazquez N, Del Rio P, Aiastui A et al. Leucine-rich repeat kinase 2 modulates cyclooxygenase 2 and the inflammatory response in idiopathic and genetic Parkinson's disease. Neurobiol Aging 2014; 35 (5): 1116-1124.
[153] Lovering R, Hanson IM, Borden KL, Martin S, O'Reilly NJ, Evan GI et al. Identification and Preliminary Characterization of a Protein Motif Related to the Zinc Finger. PNAS 1993; 90 (6): 2112-2116.
[154] Lowe J, McDermott H, Landon M, Mayer RJ, Wilkinson KD. Ubiquitin carboxyl-terminal hydrolase (PGP 9.5) is selectively present in ubiquitinated inclusion bodies characteristic of human neurodegenerative diseases. J Pathol 1990; 161 (2): 153-160.
[155] Lubbe S, Morris HR. Recent advances in Parkinson's disease genetics. J Neurol 2014; 261 (2): 259-266.
[156] Lucking CB, Durr A, Bonifati V, Vaughan J, De Michele G, Gasser T et al. Association between Early-Onset Parkinson's Disease and Mutations in the Parkin Gene. N Engl J Med 2000; 342 (21): 1560-1567.
[157] Luk KC, Kehm V, Carroll J, Zhang B, O'Brien P, Trojanowski JQ et al. Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 2012; 338 (6109): 949-953.
[158] Luoma PT, Eerola J, Ahola S, Hakonen AH, Hellstrom O, Kivisto KT et al. Mitochondrial DNA polymerase gamma variants in idiopathic sporadic Parkinson disease. Neurology 2007; 69 (11): 1152-1159.
[159] MacArthur DG, Manolio TA, Dimmock DP, Rehm HL, Shendure J, Abecasis GR et al. Guidelines for investigating causality of sequence variants in human disease. Nature 2014; 508 (7497): 469-476.
[160] Machida Y, Chiba T, Takayanagi A, Tanaka Y, Asanuma M, Ogawa N et al. Common anti-apoptotic roles of parkin and alpha-synuclein in human dopaminergic cells. Biochem Biophys Res Commun 2005; 332 (1): 233-240.
[161] Manning-Bog AB, McCormack AL, Li J, Uversky VN, Fink AL, Di Monte DA. The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein. J Biol Chem 2002; 277 (3): 1641-1644.
[162] Manzoni C, Mamais A, Dihanich S, McGoldrick P, Devine MJ, Zerle J et al. Pathogenic Parkinson's disease mutations across the functional domains of LRRK2 alter the autophagic/lysosomal response to starvation. Biochem Biophys Res Commun 2013; 441 (4): 862-866.
[163] Maraganore DM, de Andrade M, Elbaz A, Farrer MJ, Ioannidis JP, Kruger R et al. Collaborative Analysis of {alpha}-Synuclein Gene Promoter Variability and Parkinson Disease. JAMA 2006; 296 (6): 661-670.
[164] Marder KS, Tang MX, Mejia-Santana H, Rosado L, Louis ED, Comella CL et al. Predictors of parkin mutations in early-onset Parkinson disease: the consortium on risk for early-onset Parkinson disease study. Arch Neurol 2010; 67 (6): 731-738.
[165] Martin LJ. Biology of mitochondria in neurodegenerative diseases. Prog Mol Biol Transl Sci 2012; 107 355-415.
[166] Martins LM, Iaccarino I, Tenev T, Gschmeissner S, Totty NF, Lemoine NR et al. The serine protease Omi/HtrA2 regulates apoptosis by binding XIAP through a reaper-like motif. J Biol Chem 2002; 277 (1): 439-444.
[167] Matta S, Van Kolen K, da Cunha R, van den Bogaart G, Mandemakers W, Miskiewicz K et al. LRRK2 controls an EndoA phosphorylation cycle in synaptic endocytosis. Neuron 2012; 75 (6): 1008-1021.
[168] McGough IJ, Cullen PJ. Recent advances in retromer biology. Traffic 2011; 12 (8): 963-971.
[169] McNeill A, Duran R, Hughes DA, Mehta A, Schapira AH. A clinical and family history study of Parkinson's disease in heterozygous glucocerebrosidase mutation carriers. J Neurol Neurosurg Psychiatry 2012; 83 (8): 853-854.
[170] Mellick GD, Siebert GA, Funayama M, Buchanan DD, Li Y, Imamichi Y et al. Screening PARK genes for mutations in early-onset Parkinson's disease patients from Queensland, Australia. Parkinsonism Relat Disord 2009; 15 (2): 105-109.
[171] Metzker ML. Sequencing technologies - the next generation. Nat Rev Genet 2010; 11 (1): 31-46.
[172] Mills RD, Sim CH, Mok SS, Mulhern TD, Culvenor JG, Cheng HC. Biochemical aspects of the neuroprotective mechanism of PTEN-induced kinase-1 (PINK1). J Neurochem 2008; 105 (1): 18-33.
[173] Miyake Y, Tanaka K, Fukushima W, Kiyohara C, Sasaki S, Tsuboi Y et al. UCHL1 S18Y variant is a risk factor for Parkinson's disease in Japan. BMC Neurol 2012; 12 62.
[174] Monroy-Jaramillo N, Guerrero-Camacho JL, Rodriguez-Violante M, Boll-Woehrlen MC, Yescas-Gomez P, Alonso-Vilatela ME et al. Genetic mutations in early-onset Parkinson's disease Mexican patients: molecular testing implications. Am J Med Genet B Neuropsychiatr Genet 2014; 165B (3): 235-244.
[175] Morgan NV, Westaway SK, Morton JE, Gregory A, Gissen P, Sonek S et al. PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Nat Genet 2006; 38 (7): 752-754.
[176] Mougenot AL, Nicot S, Bencsik A, Morignat E, Verchere J, Lakhdar L et al. Prion-like acceleration of a synucleinopathy in a transgenic mouse model. Neurobiol Aging 2012; 33 (9): 2225-2228.
[177] Moura KC, Campos Junior M, de Rosso AL, Nicaretta DH, Pereira JS, Silva DJ et al. Genetic analysis of PARK2 and PINK1 genes in Brazilian patients with early-onset Parkinson's disease. Dis Markers 2013; 35 (3): 181-185.
[178] Mueller JC, Fuchs J, Hofer A, Zimprich A, Lichtner P, Illig T et al. Multiple regions of alpha-synuclein are associated with Parkinson's disease. Ann Neurol 2005; 57 (4): 535-541.
[179] Munishkina LA, Phelan C, Uversky VN, Fink AL. Conformational behavior and aggregation of alpha-synuclein in organic solvents: modeling the effects of membranes. Biochemistry 2003; 42 (9): 2720-2730.
[180] Murakami T, Moriwaki Y, Kawarabayashi T, Nagai M, Ohta Y, Deguchi K et al. PINK1, a gene product of PARK6, accumulates in {alpha}-synucleinopathy brains. J Neurol Neurosurg Psychiatry 2007; 78 (6): 653-654.
[181] Murphy KE, Gysbers AM, Abbott SK, Tayebi N, Kim WS, Sidransky E et al. Reduced glucocerebrosidase is associated with increased alpha-synuclein in sporadic Parkinson's disease. Brain 2014; 137 (Pt 3): 834-848.
[182] Mutez E, Nkiliza A, Belarbi K, de Broucker A, Vanbesien-Mailliot C, Bleuse S et al. Involvement of the immune system, endocytosis and EIF2 signaling in both genetically determined and sporadic forms of Parkinson's disease. Neurobiol Dis 2014; 63 165-170.
[183] Myhre R, Toft M, Kachergus J, Hulihan MM, Aasly JO, Klungland H et al. Multiple alpha-synuclein gene polymorphisms are associated with Parkinson's disease in a Norwegian population. Acta Neurol Scand 2008; 118 (5): 320-327.
[184] Nagakubo D, Taira T, Kitaura H, Ikeda M, Tamai K, Iguchi-Ariga SM et al. DJ-1, a novel oncogene which transforms mouse NIH3T3 cells in cooperation with ras. Biochem Biophys Res Commun 1997; 231 (2): 509-513.
[185] Narendra D, Tanaka A, Suen DF, Youle RJ. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 2008; 183 (5): 795-803.
[186] Neumann J, Bras J, Deas E, O'Sullivan SS, Parkkinen L, Lachmann RH et al. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease. Brain 2009; 132 (Pt 7): 1783-1794.
[187] Ozelius LJ, Senthil G, Saunders-Pullman R, Ohmann E, Deligtisch A, Tagliati M et al. LRRK2 G2019S as a Cause of Parkinson's Disease in Ashkenazi Jews. N Engl J Med 2006; 354 (4): 424-425.
[188] Padmaja MV, Jayaraman M, Srinivasan AV, Srisailapathy CR, Ramesh A. PARK2 gene mutations in early onset Parkinson's disease patients of South India. Neurosci Lett 2012; 523 (2): 145-147.
[189] Paisan-Ruiz C, Bhatia KP, Li A, Hernandez D, Davis M, Wood NW et al. Characterization of PLA2G6 as a locus for dystonia-parkinsonism. Ann Neurol 2009; 65 (1): 19-23.
[190] Paisan-Ruiz C, Guevara R, Federoff M, Hanagasi H, Sina F, Elahi E et al. Early-onset L-dopa-responsive parkinsonism with pyramidal signs due to ATP13A2, PLA2G6, FBXO7 and spatacsin mutations. Mov Disord 2010; 25 (12): 1791-1800.
[191] Paisan-Ruiz C, Jain S, Evans EW, Gilks WP, Simon J, van der Brug M et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 2004; 44 (4): 595-600.
[192] Paisan-Ruiz C, Li A, Schneider SA, Holton JL, Johnson R, Kidd D et al. Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations. Neurobiol Aging 2012; 33 (4): 814-823.
[193] Pankratz N, Nichols WC, Uniacke SK, Halter C, Murrell J, Rudolph A et al. Genome-wide linkage analysis and evidence of gene-by-gene interactions in a sample of 362 multiplex Parkinson disease families. Hum Mol Genet 2003; 12 (20): 2599-2608.
[194] Pankratz N, Pauciulo MW, Elsaesser VE, Marek DK, Halter CA, Wojcieszek J et al. Mutations in DJ-1 are rare in familial Parkinson disease. Neurosci Lett 2006; 408 (3): 209-213.
[195] Parisiadou L, Cai H. LRRK2 function on actin and microtubule dynamics in Parkinson disease. Commun Integr Biol 2010; 3 (5): 396-400.
[196] Patil KS, Basak I, Lee S, Abdullah R, Larsen JP, Moller SG. PARK13 regulates PINK1 and subcellular relocation patterns under oxidative stress in neurons. J Neurosci Res 2014;
[197] Perera RM, Zoncu R, Lucast L, De Camilli P, Toomre D. Two synaptojanin 1 isoforms are recruited to clathrin-coated pits at different stages. Proc Natl Acad Sci U S A 2006; 103 (51): 19332-19337.
[198] Periquet M, Latouche M, Lohmann E, Rawal N, De Michele G, Ricard S et al. Parkin mutations are frequent in patients with isolated early-onset parkinsonism. Brain 2003; 126 (Pt 6): 1271-1278.
[199] Petit A, Kawarai T, Paitel E, Sanjo N, Maj M, Scheid M et al. Wild-type PINK1 Prevents Basal and Induced Neuronal Apoptosis, a Protective Effect Abrogated by Parkinson Disease-related Mutations. J Biol Chem 2005; 280 (40): 34025-34032.
[200] Pilsl A, Winklhofer KF. Parkin, PINK1 and mitochondrial integrity: emerging concepts of mitochondrial dysfunction in Parkinson's disease. Acta Neuropathol 2012; 123 (2): 173-188.
[201] Plun-Favreau H, Klupsch K, Moisoi N, Gandhi S, Kjaer S, Frith D et al. The mitochondrial protease HtrA2 is regulated by Parkinson's disease-associated kinase PINK1. Nat Cell Biol 2007; 9 (11): 1243-1252.
[202] Podhajska A, Musso A, Trancikova A, Stafa K, Moser R, Sonnay S et al. Common pathogenic effects of missense mutations in the P-type ATPase ATP13A2 (PARK9) associated with early-onset parkinsonism. PLoS ONE 2012; 7 (6): e39942.
[203] Polymeropoulos MH, Higgins JJ, Golbe LI, Johnson WG, Ide SE, Di Iorio G et al. Mapping of a Gene for Parkinson's Disease to Chromosome 4q21-q23. Science 1996; 274 (5290): 1197-1199.
[204] Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A et al. Mutation in the {alpha}-Synuclein Gene Identified in Families with Parkinson's Disease. Science 1997; 276 (5321): 2045-2047.
[205] Proukakis C, Dudzik CG, Brier T, MacKay DS, Cooper JM, Millhauser GL et al. A novel alpha-synuclein missense mutation in Parkinson disease. Neurology 2013; 80 (11): 1062-1064.
[206] Quadri M, Fang M, Picillo M, Olgiati S, Breedveld GJ, Graafland J et al. Mutation in the SYNJ1 gene associated with autosomal recessive, early-onset Parkinsonism. Hum Mutat 2013; 34 (9): 1208-1215.
[207] Ramirez-Valle F, Braunstein S, Zavadil J, Formenti SC, Schneider RJ. eIF4GI links nutrient sensing by mTOR to cell proliferation and inhibition of autophagy. J Cell Biol 2008; 181 (2): 293-307.
[208] Ramirez A, Heimbach A, Grundemann J, Stiller B, Hampshire D, Cid LP et al. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet 2006; 38 (10): 1184-1191.
[209] Ramonet D, Podhajska A, Stafa K, Sonnay S, Trancikova A, Tsika E et al. PARK9-associated ATP13A2 localizes to intracellular acidic vesicles and regulates cation homeostasis and neuronal integrity. Hum Mol Genet 2012; 21 (8): 1725-1743.
[210] Rana AQ, Siddiqui I, Yousuf MS. Challenges in diagnosis of young onset Parkinson's disease. J Neurol Sci 2012; 323 (1-2): 113-116.
[211] Raquel Esteves A, Swerdlow RH, Cardoso SM. LRRK2, a puzzling protein: Insights into Parkinson's disease pathogenesis. Exp Neurol 2014;
[212] Ren Y, Zhao J, Feng J. Parkin Binds to alpha /beta Tubulin and Increases their Ubiquitination and Degradation. J Neurosci 2003; 23 (8): 3316-3324.
[213] Richardson S, Shaffer JA, Falzon L, Krupka D, Davidson KW, Edmondson D. Meta-analysis of perceived stress and its association with incident coronary heart disease. Am J Cardiol 2012; 110 (12): 1711-1716.
[214] Riley BE, Lougheed JC, Callaway K, Velasquez M, Brecht E, Nguyen L et al. Structure and function of Parkin E3 ubiquitin ligase reveals aspects of RING and HECT ligases. Nat Commun 2013; 4 1982.
[215] Rosengren A, Tibblin G, Wilhelmsen L. Self-perceived psychological stress and incidence of coronary artery disease in middle-aged men. Am J Cardiol 1991; 68 (11): 1171-1175.
[216] Ross GW, Petrovitch H, Abbott RD, Tanner CM, Popper J, Masaki K et al. Association of olfactory dysfunction with risk for future Parkinson's disease. Ann Neurol 2008; 63 (2): 167-173.
[217] Ross OA, Soto-Ortolaza AI, Heckman MG, Aasly JO, Abahuni N, Annesi G et al. Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case-control study. Lancet Neurol 2011; 10 (10): 898-908.
[218] Ross OA, Wu YR, Lee MC, Funayama M, Chen ML, Soto AI et al. Analysis of Lrrk2 R1628P as a risk factor for Parkinson's disease. Ann Neurol 2008; 64 (1): 88-92.
[219] Rothfuss O, Fischer H, Hasegawa T, Maisel M, Leitner P, Miesel F et al. Parkin protects mitochondrial genome integrity and supports mitochondrial DNA repair. Hum Mol Genet 2009; 18 (20): 3832-3850.
[220] Samaranch L, Lorenzo E, Pastor MA, Riverol M, Luquin MR, Rodriguez-Oroz MC et al. Analysis of the GIGYF2 gene in familial and sporadic Parkinson disease in the Spanish population. Eur J Neurol 2010; 17 (2): 321-325.
[221] Satake W, Nakabayashi Y, Mizuta I, Hirota Y, Ito C, Kubo M et al. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease. Nat Genet 2009; 41 (12): 1303-1307.
[222] Scarffe LA, Stevens DA, Dawson VL, Dawson TM. Parkin and PINK1: much more than mitophagy. Trends Neurosci 2014; 37 (6): 315-324.
[223] Sekeff-Sallem FA, Barbosa ER. Diagnostic pitfalls in Parkinson's disease: case report. Arq Neuropsiquiatr 2007; 65 (2A): 348-351.
[224] Sharma M, Maraganore DM, Ioannidis JP, Riess O, Aasly JO, Annesi G et al. Role of sepiapterin reductase gene at the PARK3 locus in Parkinson's disease. Neurobiol Aging 2011; 32 (11): 2108 e2101-2105.
[225] Sharma M, Mueller JC, Zimprich A, Lichtner P, Hofer A, Leitner P et al. The sepiapterin reductase gene region reveals association in the PARK3 locus: analysis of familial and sporadic Parkinson's disease in European populations. J Med Genet 2006; 43 (7): 557-562.
[226] Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Minoshima S et al. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet 2000; 25 (3): 302-305.
[227] Shimura H, Hattori N, Kubo S, Yoshikawa M, Kitada T, Matsumine H et al. Immunohistochemical and subcellular localization of Parkin protein: absence of protein in autosomal recessive juvenile parkinsonism patients. Ann Neurol 1999; 45 (5): 668-672.
[228] Shimura H, Schlossmacher MG, Hattori N, Frosch MP, Trockenbacher A, Schneider R et al. Ubiquitination of a New Form of alpha -Synuclein by Parkin from Human Brain: Implications for Parkinson's Disease. Science 2001; 293 (5528): 263-269.
[229] Shin JH, Ko HS, Kang H, Lee Y, Lee YI, Pletinkova O et al. PARIS (ZNF746) repression of PGC-1alpha contributes to neurodegeneration in Parkinson's disease. Cell 2011; 144 (5): 689-702.
[230] Shojaee S, Sina F, Banihosseini SS, Kazemi MH, Kalhor R, Shahidi GA et al. Genome-wide linkage analysis of a Parkinsonian-pyramidal syndrome pedigree by 500 K SNP arrays. Am J Hum Genet 2008; 82 (6): 1375-1384.
[231] Schlitter AM, Kurz M, Larsen JP, Woitalla D, Muller T, Epplen JT et al. Parkin gene variations in late-onset Parkinson's disease: comparison between Norwegian and German cohorts. Acta Neurol Scand 2006; 113 (1): 9-13.
[232] Schon EA, Przedborski S. Mitochondria: the next (neurode)generation. Neuron 2011; 70 (6): 1033-1053.
[233] Schrag A, Ben-Shlomo Y, Brown R, Marsden CD, Quinn N. Young-onset Parkinson's disease revisited--clinical features, natural history, and mortality. Mov Disord 1998; 13 (6): 885-894.
[234] Schrag A, Schott JM. Epidemiological, clinical, and genetic characteristics of early-onset parkinsonism. Lancet Neurol 2006; 5 (4): 355-363.
[235] Schulz JB, Falkenburger BH. Neuronal pathology in Parkinson's disease. Cell Tissue Res 2004; 318 (1): 135-147.
[236] Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N Engl J Med 2009; 361 (17): 1651-1661.
[237] Silvera D, Arju R, Darvishian F, Levine PH, Zolfaghari L, Goldberg J et al. Essential role for eIF4GI overexpression in the pathogenesis of inflammatory breast cancer. Nat Cell Biol 2009; 11 (7): 903-908.
[238] Simon-Sanchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, Berg D et al. Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat Genet 2009; 41 (12): 1308-1312.
[239] Simon-Sanchez J, Singleton AB. Sequencing analysis of OMI/HTRA2 shows previously reported pathogenic mutations in neurologically normal controls. Hum Mol Genet 2008; 17 (13): 1988-1993.
[240] Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J et al. {alpha}-Synuclein Locus Triplication Causes Parkinson's Disease. Science 2003; 302 (5646): 841-.
[241] Singleton AB, Farrer MJ, Bonifati V. The genetics of Parkinson's disease: progress and therapeutic implications. Mov Disord 2013; 28 (1): 14-23.
[242] Smith WW, Margolis RL, Li X, Troncoso JC, Lee MK, Dawson VL et al. {alpha}-Synuclein Phosphorylation Enhances Eosinophilic Cytoplasmic Inclusion Formation in SH-SY5Y Cells. J Neurosci 2005; 25 (23): 5544-5552.
[243] Smith WW, Pei Z, Jiang H, Dawson VL, Dawson TM, Ross CA. Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nat Neurosci 2006; 9 (10): 1231-1233.
[244] Spatola M, Wider C. Genetics of Parkinson's disease: the yield. Parkinsonism Relat Disord 2014; 20 Suppl 1 S35-38.
[245] Spica V, Pekmezovic T, Svetel M, Kostic VS. Prevalence of non-motor symptoms in young-onset versus late-onset Parkinson's disease. J Neurol 2013; 260 (1): 131-137.
[246] Spiess C, Beil A, Ehrmann M. A temperature-dependent switch from chaperone to protease in a widely conserved heat shock protein. Cell 1999; 97 (3): 339-347.
[247] Spillantini MG, Goedert M. Tau pathology and neurodegeneration. Lancet Neurol 2013; 12 (6): 609-622.
[248] Srivastava A, Tang MX, Mejia-Santana H, Rosado L, Louis ED, Caccappolo E et al. The relation between depression and parkin genotype: the CORE-PD study. Parkinsonism Relat Disord 2011; 17 (10): 740-744.
[249] Staropoli JF, McDermott C, Martinat C, Schulman B, Demireva E, Abeliovich A. Parkin is a component of an SCF-like ubiquitin ligase complex and protects postmitotic neurons from kainate excitotoxicity. Neuron 2003; 37 (5): 735-749.
[250] Stichel CC, Augustin M, Kuhn K, Zhu XR, Engels P, Ullmer C et al. Parkin expression in the adult mouse brain. Eur J Neurosci 2000; 12 (12): 4181-4194.
[251] Stochl J, Hagtvet KA, Brozova H, Klempir J, Roth J, Ruzicka E. Handedness does not predict side of onset of motor symptoms in Parkinson's disease. Mov Disord 2009; 24 (12): 1836-1839.
[252] Strauss KM, Martins LM, Plun-Favreau H, Marx FP, Kautzmann S, Berg D et al. Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease. Hum Mol Genet 2005; 14 (15): 2099-2111.
[253] Sun M, Latourelle JC, Wooten GF, Lew MF, Klein C, Shill HA et al. Influence of Heterozygosity for Parkin Mutation on Onset Age in Familial Parkinson Disease: The GenePD Study. Arch Neurol 2006; 63 (6): 826-832.
[254] Swinn L, Schrag A, Viswanathan R, Bloem BR, Lees A, Quinn N. Sweating dysfunction in Parkinson's disease. Mov Disord 2003; 18 (12): 1459-1463.
[255] Tan EK, Shen H, Tan LC, Farrer M, Yew K, Chua E et al. The G2019S LRRK2 mutation is uncommon in an Asian cohort of Parkinson's disease patients. Neurosci Lett 2005; 384 (3): 327-329.
[256] Tan EK, Yew K, Chua E, Puvan K, Shen H, Lee E et al. PINK1 mutations in sporadic early-onset Parkinson's disease. Mov Disord 2006; 21 (6): 789-793.
[257] Tanaka K, Matsuda N. Proteostasis and neurodegeneration: the roles of proteasomal degradation and autophagy. Biochim Biophys Acta 2014; 1843 (1): 197-204.
[258] Tassin J, Durr A, Bonnet AM, Gil R, Vidailhet M, Lucking CB et al. Levodopa-responsive dystonia. GTP cyclohydrolase I or parkin mutations? Brain 2000; 123 ( Pt 6) 1112-1121.
[259] Tayebi N, Callahan M, Madike V, Stubblefield BK, Orvisky E, Krasnewich D et al. Gaucher disease and parkinsonism: a phenotypic and genotypic characterization. Mol Genet Metab 2001; 73 (4): 313-321.
[260] Tayebi N, Walker J, Stubblefield B, Orvisky E, LaMarca ME, Wong K et al. Gaucher disease with parkinsonian manifestations: does glucocerebrosidase deficiency contribute to a vulnerability to parkinsonism? Mol Genet Metab 2003; 79 (2): 104-109.
[261] Thomas B, Beal MF. Parkinson's disease. Hum Mol Genet 2007; 16 Spec No. 2 R183-194.
[262] Tobin JE, Latourelle JC, Lew MF, Klein C, Suchowersky O, Shill HA et al. Haplotypes and gene expression implicate the MAPT region for Parkinson disease: the GenePD Study. Neurology 2008; 71 (1): 28-34.
[263] Tsunemi T, Krainc D. Zn2+ dyshomeostasis caused by loss of ATP13A2/PARK9 leads to lysosomal dysfunction and alpha-synuclein accumulation. Hum Mol Genet 2014; 23 (11): 2791-2801.
[264] Tucci A, Charlesworth G, Sheerin UM, Plagnol V, Wood NW, Hardy J. Study of the genetic variability in a Parkinson's Disease gene: EIF4G1. Neurosci Lett 2012; 518 (1): 19-22.
[265] Twelves D, Perkins KS, Counsell C. Systematic review of incidence studies of Parkinson's disease. Mov Disord 2003; 18 (1): 19-31.
[266] Ungewickell E, Ungewickell H, Holstein SE, Lindner R, Prasad K, Barouch W et al. Role of auxilin in uncoating clathrin-coated vesicles. Nature 1995; 378 (6557): 632-635.
[267] Usenovic M, Knight AL, Ray A, Wong V, Brown KR, Caldwell GA et al. Identification of novel ATP13A2 interactors and their role in alpha-synuclein misfolding and toxicity. Hum Mol Genet 2012a; 21 (17): 3785-3794.
[268] Usenovic M, Tresse E, Mazzulli JR, Taylor JP, Krainc D. Deficiency of ATP13A2 leads to lysosomal dysfunction, alpha-synuclein accumulation, and neurotoxicity. J Neurosci 2012b; 32 (12): 4240-4246.
[269] Uversky VN. A protein-chameleon: conformational plasticity of alpha-synuclein, a disordered protein involved in neurodegenerative disorders. J Biomol Struct Dyn 2003; 21 (2): 211-234.
[270] Uversky VN, Li J, Fink AL. Evidence for a partially folded intermediate in alpha-synuclein fibril formation. J Biol Chem 2001a; 276 (14): 10737-10744.
[271] Uversky VN, Li J, Fink AL. Metal-triggered structural transformations, aggregation, and fibrillation of human alpha-synuclein. A possible molecular NK between Parkinson's disease and heavy metal exposure. J Biol Chem 2001b; 276 (47): 44284-44296.
[272] Valente EM, Abou-Sleiman PM, Caputo V, Muqit MMK, Harvey K, Gispert S et al. Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1. Science 2004a; 304 (5674): 1158-1160.
[273] Valente EM, Bentivoglio AR, Dixon PH, Ferraris A, Ialongo T, Frontali M et al. Localization of a novel locus for autosomal recessive early-onset parkinsonism, PARK6, on human chromosome 1p35-p36. Am J Hum Genet 2001; 68 (4): 895-900.
[274] Valente EM, Salvi S, Ialongo T, Marongiu R, Elia AE, Caputo V et al. PINK1 mutations are associated with sporadic early-onset parkinsonism. Ann Neurol 2004b; 56 (3): 336-341.
[275] van de Warrenburg BPC, Lammens M, Lucking CB, Denefle P, Wesseling P, Booij J et al. Clinical and pathologic abnormalities in a family with parkinsonism and parkin gene mutations. Neurology 2001; 56 (4): 555-557.
[276] Van Den Eeden SK, Tanner CM, Bernstein AL, Fross RD, Leimpeter A, Bloch DA et al. Incidence of Parkinson's disease: variation by age, gender, and race/ethnicity. Am J Epidemiol 2003; 157 (11): 1015-1022.
[277] van der Walt JM, Nicodemus KK, Martin ER, Scott WK, Nance MA, Watts RL et al. Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease. Am J Hum Genet 2003; 72 (4): 804-811.
[278] van Duijn CM, Dekker MC, Bonifati V, Galjaard RJ, Houwing-Duisterma JJ, Snijders PJ et al. Park7, a novel locus for autosomal recessive early-onset parkinsonism, on chromosome 1p36. Am J Hum Genet 2001; 69 (3): 629-634.
[279] Venderova K, Kabbach G, Abdel-Messih E, Zhang Y, Parks RJ, Imai Y et al. Leucine-Rich Repeat Kinase 2 interacts with Parkin, DJ-1 and PINK-1 in a Drosophila melanogaster model of Parkinson's disease. Hum Mol Genet 2009; 18 (22): 4390-4404.
[280] Venderova K, Park DS. Programmed cell death in Parkinson's disease. Cold Spring Harb Perspect Med 2012; 2 (8):
[281] Vilarino-Guell C, Wider C, Ross OA, Dachsel JC, Kachergus JM, Lincoln SJ et al. VPS35 mutations in Parkinson disease. Am J Hum Genet 2011; 89 (1): 162-167.
[282] Vogiatzi T, Xilouri M, Vekrellis K, Stefanis L. Wild type alpha-synuclein is degraded by chaperone-mediated autophagy and macroautophagy in neuronal cells. J Biol Chem 2008; 283 (35): 23542-23556.
[283] Wakabayashi K, Tanji K, Mori F, Takahashi H. The Lewy body in Parkinson's disease: molecules implicated in the formation and degradation of alpha-synuclein aggregates. Neuropathology 2007; 27 (5): 494-506.
[284] Walter U, Klein C, Hilker R, Benecke R, Pramstaller PP, Dressler D. Brain parenchyma sonography detects preclinical parkinsonism. Mov Disord 2004; 19 (12): 1445-1449.
[285] Wan JY, Edwards KL, Hutter CM, Mata IF, Samii A, Roberts JW et al. Association mapping of the PARK10 region for Parkinson's disease susceptibility genes. Parkinsonism Relat Disord 2014; 20 (1): 93-98.
[286] Wang C, Ko HS, Thomas B, Tsang F, Chew KCM, Tay S-P et al. Stress-induced alterations in parkin solubility promote parkin aggregation and compromise parkin's protective function. Hum Mol Genet 2005a; 14 (24): 3885-3897.
[287] Wang C, Tan JM, Ho MW, Zaiden N, Wong SH, Chew CL et al. Alterations in the solubility and intracellular localization of parkin by several familial Parkinson's disease-linked point mutations. J Neurochem 2005b; 93 (2): 422-431.
[288] Wang L, Xie C, Greggio E, Parisiadou L, Shim H, Sun L et al. The chaperone activity of heat shock protein 90 is critical for maintaining the stability of leucine-rich repeat kinase 2. J Neurosci 2008; 28 (13): 3384-3391.
[289] Wang X, Winter D, Ashrafi G, Schlehe J, Wong YL, Selkoe D et al. PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility. Cell 2011; 147 (4): 893-906.
[290] Weiner WJ. There is no Parkinson disease. Arch Neurol 2008; 65 (6): 705-708.
[291] Wickremaratchi MM, Ben-Shlomo Y, Morris HR. The effect of onset age on the clinical features of Parkinson's disease. Eur J Neurol 2009; 16 (4): 450-456.
[292] Williams DR, Hadeed A, al-Din AS, Wreikat AL, Lees AJ. Kufor Rakeb disease: autosomal recessive, levodopa-responsive parkinsonism with pyramidal degeneration, supranuclear gaze palsy, and dementia. Mov Disord 2005; 20 (10): 1264-1271.
[293] Winder-Rhodes SE, Evans JR, Ban M, Mason SL, Williams-Gray CH, Foltynie T et al. Glucocerebrosidase mutations influence the natural history of Parkinson's disease in a community-based incident cohort. Brain 2013; 136 (Pt 2): 392-399.
[294] Wong ESP, Tan JMM, Wang C, Zhang Z, Tay S-P, Zaiden N et al. Relative Sensitivity of Parkin and Other Cysteine-containing Enzymes to Stress-induced Solubility Alterations. J Biol Chem 2007; 282 (16): 12310-12318.
[295] Yu S, Ueda K, Chan P. Alpha-synuclein and dopamine metabolism. Mol Neurobiol 2005; 31 (1-3): 243-254.
[296] Zabetian CP, Hutter CM, Factor SA, Nutt JG, Higgins DS, Griffith A et al. Association analysis of MAPT H1 haplotype and subhaplotypes in Parkinson's disease. Ann Neurol 2007; 62 (2): 137-144.
[297] Zarate-Lagunes M, Gu WJ, Blanchard V, Francois C, Muriel MP, Mouatt-Prigent A et al. Parkin immunoreactivity in the brain of human and non-human primates: an immunohistochemical analysis in normal conditions and in Parkinsonian syndromes. J Comp Neurol 2001; 432 (2): 184-196.
[298] Zarranz JJ, Alegre J, Gomez-Esteban JC, Lezcano E, Ros R, Ampuero I et al. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 2004; 55 (2): 164-173.
[299] Zhang Y, Gao J, Chung KKK, Huang H, Dawson VL, Dawson TM. Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. PNAS 2000; 97 (24): 13354-13359.
[300] Zhang Y, Wang ZZ, Sun HM. Lack of association between p.Ser167Asn variant of Parkin and Parkinson's disease: a meta-analysis of 15 studies involving 2,280 cases and 2,459 controls. Am J Med Genet B Neuropsychiatr Genet 2012a; 159B (1): 38-47.
[301] Zhang Y, Wang ZZ, Sun HM. Meta-analysis of the influence of Parkin p.Asp394Asn variant on the susceptibility of Parkinson's disease. Neurosci Lett 2012b; 524 (1): 60-64.
[302] Zhang Y, Wang ZZ, Sun HM. A meta-analysis of the relationship of the Parkin p.Val380Leu polymorphism to Parkinson's disease. Am J Med Genet B Neuropsychiatr Genet 2013; 162B (3): 235-244.
[303] Zhao T, De Graaff E, Breedveld GJ, Loda A, Severijnen LA, Wouters CH et al. Loss of nuclear activity of the FBXO7 protein in patients with parkinsonian-pyramidal syndrome (PARK15). PLoS ONE 2011; 6 (2): e16983.
[304] Zhou CQ, Zhang JW, Wang M, Peng GG. Meta-analysis of the efficacy and safety of long-acting non-ergot dopamine agonists in Parkinson's disease. J Clin Neurosci 2014; 21 (7): 1094-1101.
[305] Zhou W, Freed CR. DJ-1 Up-regulates Glutathione Synthesis during Oxidative Stress and Inhibits A53T {alpha}-Synuclein Toxicity. J Biol Chem 2005; 280 (52): 43150-43158.
[306] Zimprich A, Benet-Pages A, Struhal W, Graf E, Eck SH, Offman MN et al. A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. Am J Hum Genet 2011; 89 (1): 168-175.
Předběžná náplň práce
Úvod:Mutace genu parkin (PARK2), asociované s autozomálně recesivní Parkinsonovou nemocí s časným začátkem (EOPD), mají v různých populacích variabilní četnost. Cílem této práce je popsat fenotypovou charakteristiku českých pacientů s EOPD, zhodnotit vliv faktorů vnějšího prostředí na riziko onemocnění a určit frekvenci alelických variant parkinu ve skupině pacientů a kontrol.
Metodika:Celkem u 70 pacientů s EOPD (věk při vzniku nemoci ≤ 40 let) a 75 kontrol byla provedena fenotypová charakteristika a analýza alelických variant parkinu.
Výsledky:V souboru nemocných byly zachyceny tyto hlavní fenotypové rysy: absence kognitivního deficitu, častý výskyt dystonie, deprese a hyperhidrózy, výborná odpovídavost na dopaminergní léčbu, brzký rozvoj polékových dyskinezí a hybných fluktuací. Pacienti s mutacemi parkinu měli signifikantně nižší věk při vzniku onemocnění. Práce v zemědělství a expozice chemikáliím byly spojeny s vyšším rizikem EOPD, naopak pití kávy představovalo protektivní faktor. Mutace parkinu jsme identifikovali u pěti pacientů (7.1%): bodová mutace p.R334C byla přítomna u jednoho nemocného, čtyři pacienti měli exonové delece. Kromě jedné homozygotní delece exonu 4, se všechny nalezené mutace nacházely v heterozygotní konstituci. V kontrolní skupině mutace zachyceny nebyly. Polymorfismy p.S167N a p.D394N byly přítomny v podobném procentu mezi pacienty i kontrolami, polymorfismus p.V380L se vyskytoval s téměř dvakrát vyšší frekvencí v kontrolní skupině, kde jsme také zachytili novou alelickou variantu p.V380I.
Závěr:Klinická charakteristika pacientů odpovídá předchozím popisům fenotypu EOPD. Nízká prevalence mutací parkinu svědčí pro úlohu dalších genů v patogenezi onemocnění u slovanské populace.
Předběžná náplň práce v anglickém jazyce
Objective:Mutations in the parkin (PARK2) gene have been associated with autosomal recessive early-onset Parkinson’s disease (EOPD) with various frequencies in different populations. The aim of the study is to describe phenotypic characteristics of Czech EOPD patients, to evaluate the influence of environmental risk factors, and to determine the frequency of parkin allelic variants in patients and healthy controls.
Methods:A total of 70 EOPD patients (age at onset ≤ 40 years) and 75 controls were phenotyped and screened for the sequence variants and exon rearrangements in the parkin gene.
Results:The main features in the phenotype of the patients’ sample were: the absence of cognitive deficit, high occurrence of dystonia, depression, hyperhidrosis, an excellent response to dopaminergic therapy, early onset of dyskinesia and motor fluctuation. Patients with mutations in the parkin gene had significantly lower age at onset. The agricultural occupation and work with chemicals increased the risk of EOPD, however the coffee drinking appeared to be a protective factor. Parkin mutations were identified in five patients (7.1%): the p.R334C point mutation was present in one patient, four patients had exon deletions. The detected mutations were observed in the heterozygous state except one homozygous deletion of the exon 4. No mutations were obtained in control subjects. A novel sequence variant p.V380I (c.1138G>A) was identified in one control. Polymorphisms p.S167N and p.D394N were seen in similar percentage in patients and controls, polymorphism p.V380L was almost twice as frequent in controls as in patients.
Conclusions:The clinical characteristics of patients correspond to previous descriptions of EOPD phenotype. Our study contributes to the growing body of evidence on the low frequency of the parkin mutations in the EOPD suggesting the potential role of other genes in the pathogenesis of the disease in Slavic population.
 
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