The Genetics of Parkinson’s Disease

1. de La u LM, Breteler MM. Epidemi ology of Parkinson‘s dise ase. Lancet Ne urol 2006; 5(6): 525– 535.

2. Jankovic J. Parkinson‘s dise ase: clinical fe atures and di agnosis. J Ne urol Ne urosurg Psychi atry 2008; 79(4): 368– 376.

3. Schulz JB, Falkenburger BH. Ne uronal pathology in Parkinson‘s dise ase. Cell Tissue Res 2004; 318(1): 135– 147.

4. Wakabayashi K, Tanji K, Mori F, Takahashi H. The Lewy body in Parkinson‘s dise ase: molecules implicated in the formati on and degradati on of alpha‑ synuclein aggregates. Ne uropathology 2007; 27(5): 494– 506.

5. Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Ste ur EN, Braak E. Staging of brain pathology related to sporadic Parkinson‘s dise ase. Ne urobi ol Aging 2003; 24(2): 197– 211.

6. McNa ught KS, Olanow CW. Protein aggregati on in the pathogenesis of famili al and sporadic Parkinson‘s dise ase. Ne urobi ol Aging 2006; 27(4): 530– 545.

7. McNa ught KS, Jackson T, JnoBaptiste R, Kapustin A,Olanow CW. Prote asomal dysfuncti on in sporadic Parkinson‘s dise ase. Ne urology 2006; 66 (10 Suppl 4): S37– S49.

8. Onyango IG. Mitochondri al dysfuncti on and oxidative stress in Parkinson‘s dise ase. Ne urochem Res 2008; 33(3): 589– 597.

9. Tansey MG, McCoy MK, Frank‑ Cannon TC. Ne uro inflammatory mechanisms in Parkinson‘s dise ase: potenti al environmental triggers, pathways, and targets for e arly therape utic interventi on. Exp Ne urol 2007; 208(1): 1– 25.

10. Kim YS, Joh TH. Microgli a, major player in the brain inflammati on: their roles in the pathogenesis of Parkinson‘s dise ase. Exp Mol Med 2006; 38(4): 333– 347.

11. Herrup K, Yang Y. Cell cycle regulati on in the postmitotic ne uron: oxymoron or new bi ology? Nat Rev Ne urosci 2007; 8(5): 368– 378.

12. Burke RE. Programmed cell de ath and new discoveri es in the genetics of parkinsonism. J Ne urochem 2008; 104(4): 875– 890.

13. Dick FD, De Palma G, Ahmadi A, Scott NW, Prescott GJ, Bennett J et al. Environmental risk factors for Parkinson‘s dise ase and parkinsonism: the Ge oparkinson study. Occup Environ Med 2007; 64(10): 666– 672.

14. Tro ulinaki K, Tavernarakis N. Ne urodegenerative conditi ons associ ated with ageing: a molecular interplay? Mech Ageing Dev 2005; 126(1): 23– 33.

15. Tan EK, Skipper LM. Pathogenic mutati ons in Parkinson dise ase. Hum Mutat 2007; 28(7): 641– 653.

16. Schrag A, Schott JM. Epidemi ological, clinical, and genetic characteristics of e arly‑onset parkinsonism. Lancet Ne urol 2006; 5(4): 355– 363.

17. Lero ux P. Contributi on à l‘étude des ca uses de la paralysi e agitante. Paris: in Thesis 1890.

18. Gowers WR. A Manu al of Dise ases of the Nervo us System. Philadelphi a: Blakiston‘s Son 1900.

19. Polymeropo ulos MH, Higgins JJ, Golbe LI, Johnson WG, Ide SE, Di Iori o G et al. Mapping of a Gene for Parkinson‘s Dise ase to Chromosome 4q21– q23. Sci ence 1996; 274(5290): 1197– 1199.

20. Polymeropo ulos MH, Lavedan C, Leroy E, Ide SE, Deheji a A, Dutra A et al. Mutati on in the alpha‑ Synuclein Gene Identifi ed in Famili es with Parkinson‘s Dise ase. Sci ence 1997; 276(5321): 2045– 2047.

21. Krüger R, Kuhn W, Müller T, Wo italla D, Graeber M,Kösel S et al. Ala30Pro mutati on in the gene encoding alpha‑ synuclein in Parkinson‘s dise ase. Nat Genet 1998; 18(2): 106– 108.

22. Zarranz JJ, Alegre J, Gómez‑ Esteban JC, Lezcano E,Ros R, Ampuero I et al. The new mutati on, E46K, of alpha‑ synuclein ca uses Parkinson and Lewy body dementi a. Ann Ne urol 2004; 55(2): 164– 173.

23. Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J et al. Alpha‑ Synuclein Locus Triplicati on Ca uses Parkinson‘s Dise ase. Sci ence 2003; 302(5646): 841.

24. Ibáñez P, Bonnet AM, Débarges B, Lohmann E,Tison F, Pollak P et al. Ca usal relati on between alpha‑ synuclein gene duplicati on and famili al Parkinson‘s dise ase. Lancet 2004; 364(9440): 1169– 1171.

25. Pals P, Lincoln S, Manning J, Heckman M, Skipper L,Hulihan M et al. Alpha‑ Synuclein promoter confers susceptibility to Parkinson‘s dise ase. Ann Ne urol 2004; 56(4): 591– 595.

26. Uversky VN, Li J, Fink AL. Evidence for a parti ally folded intermedi ate in alpha‑ synuclein fibril formati on. J Bi ol Chem 2001; 276(14): 10737– 10744.

27. Yu S, Uéda K, Chan P. Alpha‑ synuclein and dopamine metabolism. Mol Ne urobi ol 2005; 31(1– 3): 243– 254.

28. Clayton DF, Ge orge JM. Synucleins in synaptic plasticity and ne urodegenerative disorders. J Ne urosci Res 1999; 58(1): 120– 129.

29. Uversky VN. A protein‑chamele on: conformati onal plasticity of alpha‑ synuclein, a disordered protein involved in ne urodegenerative disorders. J Bi omol Struct Dyn 2003; 21(2): 211– 234.

30. Uversky VN, Li J, Fink AL. Metal‑ triggered structural transformati ons, aggregati on, and fibrillati on of human alpha‑ synuclein. A possible molecular NK between Parkinson‘s dise ase and he avy metal exposure. J Bi ol Chem 2001; 276(47): 44284– 44296.

31. Munishkina LA, Phelan C, Uversky VN, Fink AL. Conformati onal behavi or and aggregati on of alpha‑ synuclein in organic solvents: modeling the effects of membranes. Bi ochemistry 2003; 42(9): 2720– 2730.

32. Manning‑ Bog AB, McCormack AL, Li J, Uversky VN, Fink AL, Di Monte DA. The herbicide paraqu at ca uses up‑ regulati on and aggregati on of alpha‑ synuclein in mice: paraqu at and alpha‑ synuclein. J Bi ol Chem 2002; 277(3): 1641– 1644.

33. Junn E, Ronchetti RD, Quezado MM, Kim SY, Mo uradi an MM. Tissue transglutaminase‑induced aggregati on of alpha‑ synuclein: Implicati ons for Lewy body formati on in Parkinson‘s dise ase and dementi a with Lewy bodi es. Proc Natl Acad Sci USA 2003; 100(4): 2047– 2052.

34. Smith WW, Margolis RL, Li X, Troncoso JC, Lee MK, Dawson VL et al. Alpha‑ Synuclein Phosphorylati on Enhances Eosinophilic Cytoplasmic Inclusi on Formati on in SH‑ SY5Y Cells. J Ne urosci 2005; 25(23): 5544– 5552.

35. Greenba um EA, Graves CL, Mishizen‑ Eberz AJ, Lupoli MA, Lynch DR, Englander SW et al. The E46K mutati on in alpha‑ synuclein incre ases amylo id fibril formati on. J Bi ol Chem 2005; 280(9): 7800– 7807.

36. Vogi atzi T, Xilo uri M, Vekrellis K, Stefanis L. Wild type alpha‑ synuclein is degraded by chaperone‑ medi ated a utophagy and macro a utophagy in ne uronal cells. J Bi ol Chem 2008; 283(35): 23542– 23556.

37. Bennett MC. The role of alpha‑ synuclein in ne urodegenerative dise ases. Pharmacol Ther 2005; 105(3): 311– 331.

38. Goldberg MS, Lansbury PT jr. Is there a ca use--and‑ effect relati onship between alpha‑ synuclein fibrillizati on and Parkinson‘s dise ase? Nat Cell Bi ol 2000; 2(7): E115– E119.

39. Bodner RA, Outeiro TF, Altmann S, Maxwell MM, Cho SH, Hyman BT et al. Pharmacological promoti on of inclusi on formati on: a therape utic appro ach for Huntington‘s and Parkinson‘s dise ases. Proc Natl Acad Sci USA 2006; 103(11): 4246– 4251.

40. Lee SJ. Origins and effects of extracellular alpha‑ synuclein: implicati ons in Parkinson‘s dise ase. J Mol Ne urosci 2008; 34(1): 17– 22.

41. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S et al. Mutati ons in the parkin gene ca use a utosomal recessive juvenile parkinsonism. Nature 1998; 392(6676): 605– 608.

42. Hedrich K, Kann M, Lanthaler AJ, Dalski A, Eskelson C, Landt O et al. The importance of gene dosage studi es: mutati onal analysis of the parkin gene in e arly‑onset parkinsonism. Hum Mol Genet 2001; 10(16): 1649– 1656.

43. Tan EK, Puong KY, Chan DK, Yew K, Fo ok‑ Chong S,Shen H et al. Impaired transcripti onal upregulati on of Parkin promoter vari ant under oxidative stress and prote asomal inhibiti on: clinical associ ati on. Hum Genet 2005; 118(3– 4): 484– 488.

44. Klein C, Lohmann‑Hedrich K, Rogaeva E, Schlossmacher MG, Lang AE. Deciphering the role of heterozygo us mutati ons in genes associ ated with parkinsonism. Lancet Ne urol 2007; 6(7): 652– 662.

45. Sun M, Lato urelle JC, Wo oten GF, Lew MF, Klein C,Shill HA et al. Influence of Heterozygosity for Parkin Mutati on on Onset Age in Famili al Parkinson Dise ase: The GenePD Study. Arch Ne urol 2006; 63(6): 826– 832.

46. Khan NL, Bro oks DJ, Pavese N, Sweeney MG, Wo od NW, Lees AJ et al. Progressi on of nigrostri atal dysfuncti on in a parkin kindred: an [18F]dopa PET and clinical study. Brain 2002; 125(10): 2248– 2256.

47. Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Minoshima S et al. Famili al Parkinson dise ase gene product, parkin, is a ubiquitin‑protein ligase. Nat Genet 2000; 25(3): 302– 305.

48. Imai Y, Soda M, Ino ue H, Hattori N, Mizuno Y, Takahashi R. An unfolded putative transmembrane polypeptide, which can le ad to endoplasmic reticulum stress, is a substrate of Parkin. Cell 2001; 105(7): 891– 902.

49. Shimura H, Schlossmacher MG, Hattori N, Frosch MP, Trockenbacher A, Schneider R et al. Ubiquitinati on of a New Form of alpha-Synuclein by Parkin from Human Brain: Implicati ons for Parkinson‘s Dise ase. Sci ence 2001; 293(5528): 263– 269.

50. Cha GH, Kim S, Park J, Lee E, Kim M, Lee SB et al. Parkin negatively regulates JNK pathway in the dopaminergic ne urons of Drosophila. Proc Natl Acad Sci USA 2005; 102(29): 10345– 10350.

51. 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. Bi ochem Bi ophys Res Commun 2005; 332(1): 233– 240.

52. Kitao Y, Imai Y, Ozawa K, Kataoka A, Ikeda T, Soda Met al. Pael receptor induces de ath of dopaminergic ne urons in the substanti a nigra vi a endoplasmic reticulum stress and dopamine toxicity, which is enhanced under conditi on of parkin inactivati on. Hum Mol Genet 2007; 16(1): 50– 60.

53. Henn IH, Bo uman L, Schlehe JS, Schli erf A, Schramm JE, Wegener E et al. Parkin Medi ates Ne uroprotecti on thro ugh Activati on of IkappaB Kinase/ Nucle ar Factor‑ kappaB Signaling. J Ne urosci 2007; 27(8): 1868– 1878.

54. Kuroda Y, Mitsui T, Kunishige M, Shono M, Akaike M,Azuma H et al. Parkin enhances mitochondri al bi ogenesis in proliferating cells. Hum Mol Genet 2006; 15(6): 883– 895.

55. Hampe C, Ardila‑ Osori o H, Fo urni er M, Brice A,Corti O. Bi ochemical analysis of Parkinson‘s di­sease‑ ca using vari ants of Parkin, an E3 ubiquitin‑protein ligase with mono ubiquitylati on capacity. Hum Mol Genet 2006; 15(13): 2059– 2075.

56. Wang C, Tan JM, Ho MW, Zaiden N, Wong SH, Chew CL et al. Alterati ons in the solubility and intracellular localizati on of parkin by several famili al Parkinson‘s dise ase‑linked po int mutati ons. J Ne urochem 2005; 93(2): 422– 431.

57. Wang C, Ko HS, Thomas B, Tsang F, Chew KC, Tay SP et al. Stress‑induced alterati on in parkin solubility promotes parkin aggregati on and compromise parkin‘s protective functi on. Hum Mol Genet 2005; 14: 3885– 3897.

58. Gasser T, Müller‑ Myhsok B, Wszolek ZK, Oehlmann R, Calne DB, Bonifati V et al. A susceptibility locus for Parkinson‘s dise ase maps to chromosome 2p13. Nat Genet 1998; 18(3): 262– 265.

59. Sharma M, Mueller JC, Zimprich A, Lichtner P, Hofer A, Leitner P et al. The sepi apterin reductase gene regi on reve als associ ati on in the PARK3 locus: analysis of famili al and sporadic Parkinson‘s dise ase in Europe an populati ons. J Med Genet 2006; 43(7): 557– 562.

60. Tobin JE, Cui J, Wilk JB, Lato urelle JC, Larami e JM, McKee AC et al. Sepi apterin reductase expressi on is incre ased in Parkinson‘s dise ase brain tissue. Brain Res 2007; 1139: 42– 47.

61. Leroy E, Boyer R, Auburger G, Le ube B, Ulm G, Mezey E et al. The ubiquitin pathway in Parkinson‘s dise ase. Nature 1998; 395(6701): 451– 452.

62. Carmine Belin A, Westerlund M, Bergman O, Nissbrandt H, Lind C, Sydow O et al. S18Y in ubiquitin carboxy‑terminal hydrolase L1 (UCH‑ L1) associ ated with decre ased risk of Parkinson‘s dise ase in Sweden. Parkinsonism Relat Disord 2007; 13(5): 295– 298.

63. Lowe J, McDermott H, Landon M, Mayer RJ, Wilkinson KD. Ubiquitin carboxyl‑terminal hydrolase (PGP 9.5) is selectively present in ubiquitinated inclusi on bodi es characteristic of human ne urodegenerative dise ases. J Pathol 1990; 161(2): 153– 160.

64. Li u Y, Fallon L, Lashuel HA, Li u Z, Lansbury PT Jr. The UCH‑ L1 gene encodes two opposing enzymatic activiti es that affect alpha‑ synuclein degradati on and Parkinson‘s dise ase susceptibility. Cell 2002; 111(2): 209– 218.

65. Kyratzi E, Pavlaki M, Stefanis L. The S18Y polymorphic vari ant of UCH‑ L1 confers an anti oxidant functi on to ne uronal cells. Hum Mol Genet 2008; 17(14): 2160– 2171.

66. Valente EM, Bentivogli o AR, Dixon PH, Ferraris A,Ialongo T, Frontali M et al. Localizati on of a novel locus for a utosomal recessive e arly‑onset parkinsonism, PARK6, on human chromosome 1p35– p36. Am J Hum Genet 2001; 68(4): 895– 900.

67. Valente EM, Abo u‑ Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S et al. Hereditary Early‑onset Parkinson‘s Dise ase Ca used by Mutati ons in PINK1. Sci ence 2004; 304(5674): 1158– 1160.

68. Ishihara‑Pa ul L, Hulihan MM, Kachergus J, Upmanyu R, Warren L, Amo uri R et al. PINK1 mutati ons and parkinsonism. Ne urology 2008; 71(12): 896– 902.

69. Khan NL, Valente EM, Bentivogli o AR, Wo od NW, Albanese A, Bro oks DJ et al. Clinical and subclinical dopaminergic dysfuncti on in PARK6‑linked parkinsonism: an 18F‑ dopa PET study. Ann Ne urol 2002; 52(6): 849– 853.

70. 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 Ne urol Ne urosurg Psychi atry 2007; 78(6): 653– 654.

71. Petit A, Kawarai T, Paitel E, Sanjo N, Maj M, Scheid Met al. Wild‑type PINK1 Prevents Basal and Induced Ne uronal Apoptosis, a Protective Effect Abrogated by Parkinson Dise ase‑related Mutati ons. J Bi ol Chem 2005; 280(40): 34025– 34032.

72. Yang Y, Gehrke S, Imai Y, Hu ang Z, Ouyang Y, Wang JW et al. Mitochondri al pathology and muscle and dopaminergic ne uron degenerati on ca used by inactivati on of Drosophila Pink1 is rescued by Parkin. Proc Natl Acad Sci USA 2006; 103(28): 10793– 10798.

73. Po ole AC, Thomas RE, Andrews LA, McBride HM, Whitworth AJ, Pallanck LJ. The PINK1/ Parkin pathway regulates mitochondri al morphology. Proc Natl Acad Sci USA 2008; 105(5): 1638– 1643.

74. Mills RD, Sim CH, Mok SS, Mulhern TD, Culvenor JG, Cheng HC. Bi ochemical aspects of the ne uroprotective mechanism of PTEN‑induced kinase‑ 1 (PINK1). J Ne urochem 2008; 105(1): 18– 33.

75. van Duijn CM, Dekker MC, Bonifati V, Galjaard RJ, Ho uwing‑ Duistermaat JJ, Snijders PJ et al. Park7, a novel locus for a utosomal recessive e arly‑onset parkinsonism, on chromosome 1p36. Am J Hum Genet 2001; 69(3): 629– 634.

76. Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Kri eger E et al. Mutati ons in the DJ‑ 1 Gene Associ ated with Autosomal Recessive Early‑onset Parkinsonism. Sci ence 2003; 299(5604): 256– 259.

77. Dekker MC, Eshuis SA, Maguire RP, Veenma‑ van der Duijn L, Pruim J, Snijders PJ et al. PET ne uro imaging and mutati ons in the DJ‑ 1 gene. J Ne ural Transm 2004; 111(12): 1575– 1581.

78. Nagakubo D, Taira T, Kita ura H, Ikeda M, Tamai K, Iguchi‑ Ariga SM et al. DJ‑ 1, a novel oncogene which transforms mo use NIH3T3 cells in co operati on with ras. Bi ochem Bi ophys Res Commun 1997; 231(2): 509– 513.

79. Lev N, Ickowicz D, Melamed E, Offen D. Oxidative insults induce DJ‑ 1 upregulati on and redistributi on: Implicati ons for ne uroprotecti on. Ne urotoxicology 2008; 29(3): 397– 405.

80. Kinumi T, Kimata J, Taira T, Ariga H, Niki E. Cysteine‑ 106 of DJ‑ 1 is the most sensitive cysteine residue to hydrogen peroxide‑ medi ated oxidati on in vivo in human umbilical vein endotheli al cells. Bi ochem Bi ophys Res Commun 2004; 317(3): 722– 728.

81. Clements CM, McNally RS, Conti BJ, Mak TW, Ting JP. DJ‑ 1, a cancer‑  and Parkinson‘s dise ase‑associ ated protein, stabilizes the anti oxidant transcripti onal master regulator Nrf2. Proc Natl Asad Sci USA 2006; 103(41): 15091– 15096.

82. Zho u W, Freed CR. DJ‑ 1 Up‑ regulates Glutathi one Synthesis during Oxidative Stress and Inhibits A53T alpha‑ Synuclein Toxicity. J Bi ol Chem 2005; 280(52): 43150– 43158.

83. Junn E, Taniguchi H, Je ong BS, Zhao X, Ichijo H, Mo uradi an MM. Interacti on of DJ‑ 1 with Daxx inhibits apoptosis signal‑ regulating kinase 1 activity and cell de ath. Proc Natl Asad Sci USA 2005; 102(27): 9691– 9696.

84. Anderson PC, Daggett V. Molecular basis for the structural instability of human DJ‑ 1 induced by the L166P mutati on associ ated with Parkinson‘s dise ase. Bi ochemistry 2008; 47(36): 9380– 9393.

85. Görner 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 Essenti al for Protein Stability and Survival Promoting Activity of DJ‑ 1. J Bi ol Chem 2007; 282(18): 13680– 13691.

86. Funayama M, Hasegawa K, Kowa H, Saito M, Tsuji S, Obata F. A new locus for Parkinson‘s dise ase (PARK8) maps to chromosome 12p11.2– q13.1. Ann Ne urol 2002; 51(3): 296– 301.

87. Paisán‑ Ruíz C, Jain S, Evans EW, Gilks WP, Simón J,van der Brug M et al. Cloning of the gene containing mutati ons that ca use PARK8‑linked Parkinson‘s dise ase. Ne uron 2004; 44(4): 595– 600.

88. Clark LN, Wang Y, Karlins E, Saito L, Meji a‑ Santana H, Harris J et al. Frequency of LRRK2 mutati ons in e arly‑  and late‑onset Parkinson dise ase. Ne urology 2006; 67(10): 1786– 1791.

89. Lesage S, Dürr A, Tazir M, Lohmann E, Le utenegger AL, Janin S et al. LRRK2 G2019S as a Ca use of Parkinson‘s Dise ase in North African Arabs. N Engl J Med 2006; 354(4): 422– 423.

90. Ozeli us LJ, Senthil G, Sa unders‑ Pullman R, Ohmann E, Deligtisch A, Tagli ati M et al. LRRK2 G2019S as a Ca use of Parkinson‘s Dise ase in Ashkenazi Jews. N Engl J Med 2006; 354(4): 424– 425.

91. Tan EK, Shen H, Tan LC, Farrer M, Yew K, Chu a E et al. The G2019S LRRK2 mutati on is uncommon in an Asi an cohort of Parkinson‘s dise ase pati ents. Ne urosci Lett 2005; 384(3): 327– 329.

92. Farrer MJ, Stone JT, Lin CH, Dächsel JC, Hulihan MM, Ha ugarvoll K et al. Lrrk2 G2385R is an ancestral risk factor for Parkinson‘s dise ase in Asi a. Parkinsonism Relat Disord 2007; 13(2): 89– 92.

93. 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 dise ase. Ann Ne urol 2008; 64(1): 88– 92.

94. Gi asson BI, Covy JP, Bonini NM, Hurtig HI, Farrer MJ, Trojanowski JQ et al. Bi ochemical and pathological characterizati on of Lrrk2. Ann Ne urol 2006; 59(2): 315– 322.

95. Häbig K, Walter M, Poths S, Ri ess O, Bonin M. RNA interference of LRRK2- micro array expressi on analysis of a Parkinson‘s dise ase key player. Ne urogenetics 2008; 9(2): 83– 94.

96. Gandhi PN, Wang X, Zhu X, Chen SG, Wilson‑ Delfosse AL. The Roc domain of le ucine‑ rich repe at kinase 2 is suffici ent for interacti on with microtubules. J Ne urosci Res 2008; 86(8): 1711– 1720.

97. Iaccarino C, Crosi o C, Vitale C, Sanna G, Carri MT, Barone P. Apoptotic mechanisms in mutant LRRK2– medi ated cell de ath. Hum Mol Genet 2007; 16(11): 1319– 1326.

98. Wang L, Xi e C, Greggi o E, Parisi ado u L, Shim H,Sun L et al. The chaperone activity of he at shock protein 90 is critical for maintaining the stability of le ucine‑ rich repe at kinase 2. J Ne urosci 2008; 28(13): 3384– 3391.

99. Smith WW, Pei Z, Ji ang H, Dawson VL, Dawson TM, Ross CA. Kinase activity of mutant LRRK2 medi ates ne uronal toxicity. Nat Ne urosci 2006; 9(10): 1231– 1233.

100. Deng J, Lewis PA, Greggi o E, Sluch E, Beilina A, Co okson MR. Structure of the ROC domain from the Parkinson‘s dise ase‑associ ated le ucine‑ rich repe at kinase 2 reve als a dimeric GTPase. Proc Natl Acad Sci USA 2008; 105(5): 1499– 1504.

101. Hampshire DJ, Roberts E, Crow Y, Bond J, Mubaidin A, Wri ekat AL et al. Kufor‑ Rakeb syndrome, pallido‑ pyramidal degenerati on with supranucle ar upgaze paresis and dementi a, maps to 1p36. J Med Genet 2001; 38(10): 680– 682.

102. Willi ams DR, Hadeed A, al‑ Din AS, Wreikat AL, Lees AJ. Kufor Rakeb dise ase: a utosomal recessive, levodopa‑ responsive parkinsonism with pyramidal degenerati on, supranucle ar gaze palsy, and dementi a. Mov Disord 2005; 20(10): 1264– 1271.

103. Ramirez A, Heimbach A, Gründemann J, Stiller B,Hampshire D, Cid LP et al. Hereditary parkinsonism with dementi a is ca used by mutati ons in ATP13A2, encoding a lysosomal type 5 P‑type ATPase. Nat Genet 2006; 38(10): 1184– 1191.

104. Di Fonzo A, Chi en HF, Socal M, Gira udo S, Tassorelli C, Iliceto G et al. ATP13A2 missense mutati ons in juvenile parkinsonism and yo ung onset Parkinson dise ase. Ne urology 2007; 68(19): 1557– 1562.

105. Hicks AA, Pétursson H, Jónsson T, Stefánsson H, Jóhannsdóttir HS, Sainz J et al. A susceptibility gene for late‑onset idi opathic Parkinson‘s dise ase. Ann Ne urol 2002; 52(5): 549– 555.

106. No ureddine MA, Li YJ, van der Walt JM, Walters R,Jewett RM, Xu H et al. Genomic convergence to identify candidate genes for Parkinson dise ase: SAGE analysis of the substanti a nigra. Mov Disord 2005; 20(10): 1299– 1309.

107. Anderson LR, Betarbet R, Ge aring M, Gulcher J,Hicks AA, Stefánsson K et al. PARK10 candidate RNF11 is expressed by vulnerable ne urons and localizes to Lewy bodi es in Parkinson dise ase brain. J Ne uropathol Exp Ne urol 2007; 66(10): 955– 964.

108. Connor MK, Seth A. A central role for the ring finger protein RNF11 in ubiquitin‑medi ated prote olysis vi a interacti ons with E2s and E3s. Oncogene 2004; 23(11): 2089– 2095.

109. Azmi P, Seth A. RNF11 is a multifuncti onal modulator of growth factor receptor signalling and transcripti onal regulati on. Eur J Cancer 2005; 41(16): 2549– 2560.

110. La uti er C, Goldwurm S, Dürr A, Gi ovannone B,Tsi aras WG, Pezzoli G et al. Mutati ons in the GIGYF2 (TNRC15) gene at the PARK11 locus in famili al Parkinson dise ase. Am J Hum Genet 2008; 82(4): 822– 833.

111. Gi ovannone B, Lee E, Lavi ola L, Gi orgino F, Cleveland KA, Smith RJ. Two novel proteins that are linked to insulin‑like growth factor (IGF‑I) receptors by the Grb10 adapter and modulate IGF‑I signaling. J Bi ol Chem 2003; 278(34): 31564– 31573.

112. Schulingkamp RJ, Pagano TC, Hung D, Raffa RB. Insulin receptors and insulin acti on in the brain: revi ew and clinical implicati ons. Ne urosci Bi obehav Rev 2000; 24(8): 855– 872.

113. Offen D, Shtaif B, Hadad D, Weizman A, Melamed E,Gil‑ Ad I. Protective effect of insulin‑like‑ growth‑ factor‑ 1 against dopamine‑induced ne urotoxicity in human and rodent ne uronal cultures: possible implicati ons for Parkinson‘s dise ase. Ne urosci Lett 2001; 316(3): 129– 132.

114. Pankratz N, Nichols WC, Uni acke SK, Halter C, Murrell J, Rudolph A et al. Genome‑ wide linkage analysis and evidence of gene‑ by‑ gene interacti ons in a sample of 362 multiplex Parkinson dise ase famili es. Hum Mol Genet 2003; 12(20): 2599– 2608.

115. Stra uss KM, Martins LM, Plun‑ Favre a u H, Marx FP, Ka utzmann S, Berg D et al. Loss of functi on mutati ons in the gene encoding Omi/ HtrA2 in Parkinson‘s dise ase. Hum Mol Genet 2005; 14(15): 2099– 2111.

116. Simón‑ Sánchez J, Singleton AB. Sequencing analysis of OMI/ HTRA2 shows previ o usly reported pathogenic mutati ons in ne urologically normal controls. Hum Mol Genet 2008; 17(13): 1988– 1993.

117. Martins LM, Iaccarino I, Tenev T, Gschmeissner S,Totty NF, Lemo ine NR et al. The serine prote ase Omi/ HtrA2 regulates apoptosis by binding XIAP thro ugh a re aper‑like motif. J Bi ol Chem 2002; 277(1): 439– 444.

118. Spi ess C, Beil A, Ehrmann M. A temperature‑dependent switch from chaperone to prote ase in a widely conserved he at shock protein. Cell 1999; 97(3): 339– 347.

119. Horvath R, Kley RA, Lochmüller H, Vorgerd M. Parkinson syndrome, ne uropathy, and myopathy ca u-sed by the mutati on A8344G (MERRF) in tRNALys. Ne u-rology 2007; 68(1): 56– 58.

120. van der Walt JM, Nicodemus KK, Martin ER, Scott WK, Nance MA, Watts RL et al. Mitochondri al polymorphisms significantly reduce the risk of Parkinson dise ase. Am J Hum Genet 2003; 72(4): 804– 811.

121. Autere J, Mo ilanen JS, Finnilä S, So ininen H, Mannermaa A, Hartikainen P et al. Mitochondri al DNA polymorphisms as risk factors for Parkinson‘s dise ase and Parkinson‘s dise ase dementi a. Hum Genet 2004; 115(1): 29– 35.

122. Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK, Perry RH et al. High levels of mitochondri al DNA deleti ons in substanti a nigra ne urons in aging and Parkinson dise ase. Nat Genet 2006; 38(5): 515– 517.

123. Kraytsberg Y, Kudryavtseva E, McKee AC, Ge ula C,Kowall NW, Khrapko K. Mitochondri al DNA deleti ons are abundant and ca use functi onal impairment in aged human substanti a nigra ne urons. Nat Genet 2006; 38(5): 518– 520.

124. Luoma PT, Eerola J, Ahola S, Hakonen AH, Hellström O, Kivistö KT et al. Mitochondri al DNA polymerase gamma vari ants in idi opathic sporadic Parkinson dise ase. Ne urology 2007; 69(11): 1152– 1159.

125. Benmoyal‑ Segal L, Soreq H. Gene‑ environment interacti ons in sporadic Parkinson‘s dise ase. J Ne urochem 2006; 97(6): 1740– 1755.

126. Yang YX, Latchman DS. Nurr1 transcripti onally regulates the expressi on of alpha‑ synuclein. Ne uroreport 2008; 19(8): 867– 871.

127. Zheng K, Heydari B, Simon DK. A common NURR1 polymorphism associ ated with Parkinson dise ase and diffuse Lewy body dise ase. Arch Ne urol 2003; 60(5): 722– 725.

128. Bembi B, Zambito Marsala S, Sidransky E, Ci ana G, Carrozzi M, Zorzon M et al. Ga ucher‘s dise ase with Parkinson‘s dise ase: clinical and pathological aspects. Ne urology 2003; 61(1): 99– 101.

129. Sato C, Morgan A, Lang AE, Salehi‑ Rad S, Kawarai T, Meng Y et al. Analysis of the glucocerebrosidase gene in Parkinson‘s dise ase. Mov Disord 2005; 20(3): 367– 370.

130. Lee HJ, Khoshaghideh F, Patel S, Lee SJ. Cle arance of alpha‑ synuclein oligomeric intermedi ates vi a the lysosomal degradati on pathway. J Ne urosci 2004; 24(8): 1888– 1896.

131. Braak H, Rüb U, Jansen Ste ur EN, Del Tredici K, de Vos RA. Cognitive status correlates with ne uropathologic stage in Parkinson dise ase. Ne urology 2005; 64(8): 1404– 1410.

132. van de Warrenburg BP, Lammens M, Lücking CB, Denèfle P, Wesseling P, Bo o ij J et al. Clinical and pathologic abnormaliti es in a family with parkinsonism and parkin gene mutati ons. Ne urology 2001; 56(4): 555– 557.

133. Zabeti an CP, Hutter CM, Factor SA, Nutt JG, Higgins DS, Griffith A et al. Associ ati on analysis of MAPT H1 haplotype and subhaplotypes in Parkinson‘s dise ase. Ann Ne urol 2007; 62(2): 137– 144.

134. Engelender S, Kaminsky Z, Guo X, Sharp AH, Amaravi RK, Kleiderlein JJ et al. Synphilin‑1 associ ates with alpha‑ synuclein and promotes the formati on of cytosolic inclusi ons. Nat Genet 1999; 22(1): 110– 114.

135. Marx FP, Holzmann C, Stra uss KM, Li L, Eberhardt O,Gerhardt E et al. Identificati on and functi onal characterizati on of a novel R621C mutati on in the synphilin‑1 gene in Parkinson‘s dise ase. Hum Mol Genet 2003; 12(11): 1223– 1231.

136. Myhre R, Klungland H, Farrer MJ, Aasly JO. Genetic associ ati on study of synphilin‑1 in idi opathic Parkinson‘s dise ase. BMC Med Genet 2008; 9: 19.

137. Gilgun‑ Sherki Y, Djaldetti R, Melamed E, Offen D. Polymorphism in candidate genes: implicati ons for the risk and tre atment of idi opathic Parkinson‘s dise ase. Pharmacogenomics J 2004; 4(5): 291– 306.

138. Tan EK, Jankovic J. Genetic testing in Parkinson dise ase: promises and pitfalls. Arch Ne urol 2006; 63(9): 1232– 1237.

139. Ishihara L, Warren L, Gibson R, Amo uri R, Lesage S,Dürr A et al. Clinical Fe atures of Parkinson Dise ase Pati ents With Homozygo us Le ucine‑ Rich Repe at Kinase 2 G2019S Mutati ons. Arch Ne urol 2006; 63(9): 1250– 1254.

140. Pramstaller PP, Schlossmacher MG, Jacques TS, Scaravilli F, Eskelson C, Pepivani I et al. Lewy body Parkinson‘s dise ase in a large pedigree with 77 Parkin mutati on carri ers. Ann Ne urol 2005; 58(3): 411– 422.

141. Weiner WJ. There is no Parkinson dise ase. Arch Ne urol 2008; 65(6): 705– 708.