LRRK2: Cause, risk, and mechanism

Journal of Parkinson's Disease

Volumn 3, Issue 2, 2013, Pages 85-103

  Paisán Ruiz, Coro ^a   Lewis, Patrick A ^b,c   Singleton, Andrew B ^d  

^a MOUNT SINAI SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY COLLEGE LONDON   (United Kingdom)

^c UNIVERSITY OF READING   (United Kingdom)

^d NATIONAL INSTITUTE ON AGING   (United States)

Author keywords

associated phenotype; biology; disease risk; future challenges; genetics; LRRK2; Parkinson's disease; parkinsonism

Indexed keywords

ALPHA SYNUCLEIN; LEUCINE RICH REPEAT KINASE 2; TAU PROTEIN;

CARBOXY TERMINAL SEQUENCE; CHAPERONE-MEDIATED AUTOPHAGY; DIMERIZATION; DISEASE ASSOCIATION; ENZYME ACTIVITY; ENZYME SPECIFICITY; GENE; GENE EXPRESSION REGULATION; GENE FREQUENCY; GENE FUNCTION; GENE LINKAGE DISEQUILIBRIUM; GENE MUTATION; GENETIC ANALYSIS; GENETIC POLYMORPHISM; GENETIC VARIABILITY; HETEROZYGOSITY; HUMAN; HYPOSMIA; IMMUNOELECTRON MICROSCOPY; LEWY BODY; LRRK2 GENE; NEUROFIBRILLARY TANGLE; NEUROPATHOLOGY; NONHUMAN; PARKINSON DISEASE; PATHOGENESIS; PHENOTYPE; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN PROTEIN INTERACTION; REVIEW; SIGNAL TRANSDUCTION;

GENETIC ASSOCIATION STUDIES; GENETIC PREDISPOSITION TO DISEASE; HUMANS; MUTATION; PARKINSON DISEASE; PROTEIN-SERINE-THREONINE KINASES;

EID: 84880214877     PISSN: 18777171     EISSN: 1877718X     Source Type: Journal    
DOI: 10.3233/JPD-130192     Document Type: Review

References (180)

1. Paisan-Ruiz C, Jain S, EvansEW, GilksWP, Simon J, van der Brug M, Lopez de Munain A, Aparicio S, Gil AM, Khan N, Johnson J, Martinez JR, Nicholl D, Carrera IM, Pena AS, de Silva R, Lees A, Marti-Masso JF, Perez-Tur J,WoodNW, & Singleton AB (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron, 44, 595-600.
2. Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, Kachergus J, Hulihan M, Uitti RJ, Calne DB, Stoessl AJ, Pfeiffer RF, Patenge N, Carbajal IC, Vieregge P, Asmus F, Muller-Myhsok B, Dickson DW, Meitinger T, Strom TM, Wszolek ZK, & Gasser T(2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron, 44, 601-607.
3. Rubio JP, Topp S, Warren L, St Jean PL, Wegmann D, Kessner D, Novembre J, Shen J, Fraser D, Aponte J, Nangle K, Cardon LR, Ehm MG, Chissoe SL, Whittaker JC, Nelson MR, & Mooser VE (2012) Deep sequencing of the LRRK2 gene in 14,002 individuals reveals evidence of purifying selection and independent origin of the p. Arg1628Pro mutation in Europe. Hum Mutat, 33, 1087-1098.
4. Aasly JO, Vilarino-Guell C, Dachsel JC, Webber PJ, West AB, Haugarvoll K, Johansen KK, Toft M, Nutt JG, Payami H, Kachergus JM, Lincoln SJ, Felic A, Wider C, Soto-Ortolaza AI, Cobb SA, White LR, Ross OA, & Farrer MJ (2010) Novel pathogenic LRRK2 p. Asn1437His substitution in familial Parkinson's disease. Mov Disord, 25, 2156-2163.
5. Bardien S, Lesage S, Brice A, & Carr J (2011) Genetic characteristics of leucine-rich repeat kinase 2 (LRRK2) associated Parkinson's disease. Parkinsonism Relat Disord, 17, 501-508.
6. Lorenzo-Betancor O, Samaranch L, Ezquerra M, Tolosa E, Lorenzo E, Irigoyen J, Gaig C, PastorMA,Soto-Ortolaza AI, Ross OA, Rodriguez-Oroz MC, Valldeoriola F, Marti MJ, Luquin MR, Perez-Tur J, Burguera JA, Obeso JA, & Pastor P (2011) LRRK2 haplotype-sharing analysis in Parkinson's disease reveals a novel p. S1761R mutation. Mov Disord, 27, 146-151.
7. Paisan-Ruiz C (2009) LRRK2 gene variation and its contribution to Parkinson disease. Hum Mutat, 30, 1153-1160.
8. Correia Guedes L, Ferreira JJ, Rosa MM, Coelho M, BonifatiV,& SampaioC(2010)Worldwide frequency of G2019S LRRK2 mutation in Parkinson's disease: A systematic review. Parkinsonism Relat Disord, 16, 237-242.
9. Bras JM, Guerreiro RJ, Ribeiro MH, Januario C, Morgadinho A, Oliveira CR, Cunha L, Hardy J, & Singleton A (2005) G2019S dardarin substitution is a common cause of Parkinson's disease in a Portuguese cohort. Mov Disord, 20, 1653-1655.
10. Lesage S, Leutenegger AL, Ibanez P, Janin S, Lohmann E, Durr A, & Brice A (2005) LRRK2 haplotype analyses in European and North African families with Parkinson disease: A common founder for the G2019S mutation dating from the 13th century. Am J Hum Genet, 77, 330-332.
11. Ozelius LJ, Senthil G, Saunders-Pullman R, Ohmann E, Deligtisch A, Tagliati M, Hunt AL, Klein C, Henick B, Hailpern SM, Lipton RB, Soto-Valencia J, Risch N,&Bressman SB (2006) LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews. N Engl J Med, 354, 424-425.
12. Deng H, Le W, Guo Y, Hunter CB, Xie W, Huang M, & Jankovic J (2006) Genetic analysis of LRRK2 mutations in patients with Parkinson disease. J Neurol Sci, 251, 102-106.
13. Mata IF, Cosentino C, Marca V, Torres L, Mazzetti P, Ortega O, Raggio V, Aljanati R, Buzo R, Yearout D, Dieguez E, & Zabetian CP (2009) LRRK2 mutations in patients with Parkinson's disease from Peru and Uruguay. Parkinsonism Relat Disord, 15, 370-373.
14. Yescas P, Lopez M, Monroy N, Boll MC, Rodriguez-Violante M, Rodriguez U, Ochoa A, & Alonso ME (2010) Low frequency of common LRRK2 mutations in Mexican patients with Parkinson's disease. Neurosci Lett, 485, 79-82.
15. Gorostidi A, Ruiz-Martinez J, Lopez de Munain A, Alzualde A, & Marti Masso JF (2009) LRRK2 G2019S and R1441G mutations associated with Parkinson's disease are common in the Basque Country, but relative prevalence is determined by ethnicity. Neurogenetics, 10, 157-159.
16. Nuytemans K, Rademakers R, Theuns J, Pals P, Engelborghs S, Pickut B, de Pooter T, Peeters K, Mattheijssens M, Van den Broeck M, Cras P, De Deyn PP, & van Broeckhoven C (2008) Founder mutation p. R1441C in the leucine-rich repeat kinase 2 gene in Belgian Parkinson's disease patients. Eur J Hum Genet, 16, 471-479.
17. Ross OA, Soto-Ortolaza AI, Heckman MG, Aasly JO, Abahuni N, Annesi G, Bacon JA, Bardien S, Bozi M, Brice A, Brighina L, Van Broeckhoven C, Carr J, Chartier-Harlin M-C, Dardiotis E, Dickson DW, Diehl NN, Elbaz A, Ferrarese C, Ferraris A, FiskeB, Gibson JM, Gibson R, Hadjigeorgiou GM, Hattori N, Ioannidis JPA, Jasinska-Myga B, Jeon BS, Kim YJ, Klein C, Kruger R, Kyratzi E, Lesage S, Lin C-H, Lynch T, Maraganore DM, Mellick GD, Mutez E, Nilsson C, Opala G, Park SS, Puschmann A, Quattrone A, Sharma M, Silburn PA, Sohn YH, Stefanis L, Tadic V, Theuns J, Tomiyama H, Uitti RJ, Valente EM, van de Loo S, Vassilatis DK, Vilariño-G̈uell C, White LR, Wirdefeldt K, Wszolek ZK, Wu R-M, & Farrer MJ (2011) Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: A case-control study. Lancet Neurol, 10, 898-908.
18. Ross OA, Spanaki C, Griffith A, Lin CH, Kachergus J, Haugarvoll K, Latsoudis H, Plaitakis A, Ferreira JJ, Sampaio C, BonifatiV,WuRM,ZabetianCP, &FarrerMJ(2009) Haplotype analysis of Lrrk2 R1441H carriers with parkinsonism. Parkinsonism Relat Disord, 15, 466-467.
19. Funayama M, Hasegawa K, Ohta E, Kawashima N, Komiyama M, Kowa H, Tsuji S, & Obata F (2005) An LRRK2 mutation as a cause for the parkinsonism in the original PARK8 family. Ann Neurol, 57, 918-921.
20. Kim JS, Cho JW, Shin H, Lee WY, Ki CS, Cho AR, & Kim HT (2012) A Korean Parkinson's disease family with the LRRK2 p. Tyr1699Cys mutation showing clinical heterogeneity. Mov Disord 27, 320-324.
21. Marras C, Schule B, Munhoz RP, Rogaeva E, Langston JW, Kasten M, Meaney C, Klein C, Wadia PM, Lim SY, Chuang RS, Zadikof C, Steeves T, Prakash KM, de Bie RM, Adeli G, Thomsen T, Johansen KK, Teive HA, Asante A, ReginoldW, & Lang AE (2011) Phenotype in parkinsonian and nonparkinsonian LRRK2 G2019S mutation carriers. Neurology, 77, 325-333.
22. Healy DG, Falchi M, O'Sullivan SS, Bonifati V, Durr A, Bressman S, Brice A, Aasly J, Zabetian CP, Goldwurm S, Ferreira JJ, Tolosa E, Kay DM, Klein C,Williams DR, Marras C, Lang AE, Wszolek ZK, Berciano J, Schapira AH, Lynch T, Bhatia KP, Gasser T, Lees AJ,&WoodNW(2008) Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: A case-control study. Lancet Neurol, 7, 583-590.
23. Aasly JO, Toft M, Fernandez-Mata I, Kachergus J, Hulihan M, White LR, & Farrer M (2005) Clinical features of LRRK2-associated Parkinson's disease in central Norway. Ann Neurol, 57, 762-765.
24. Alcalay RN, Mejia-Santana H, Tang MX, Rakitin B, Rosado L, Ross B, VerbitskyM, Kisselev S, Louis ED, Comella CL, Colcher A, Jennings D, Nance MA, Bressman S, Scott WK, Tanner C, Mickel SF, Andrews HF, Waters CH, Fahn S, Cote LJ, Frucht SJ, Ford B, Rezak M, Novak K, Friedman JH, Pfeiffer R, Marsh L, Hiner B, Siderowf A, Ottman R, Clark LN, Marder KS, & Caccappolo E (2010) Self-report of cognitive impairment and mini-mental state examination performance inPRKN,LRRK2,andGBAcarriers with early onset Parkinson's disease. J Clin Exp Neuropsychol, 32, 775-779.
25. Goldwurm S, Zini M, Di Fonzo A, De Gaspari D, Siri C, Simons EJ, van Doeselaar M, Tesei S, Antonini A, Canesi M, Zecchinelli A, Mariani C, Meucci N, Sacilotto G, Cilia R, Isaias IU, Bonetti A, Sironi F, Ricca S, Oostra BA, Bonifati V, & Pezzoli G (2006) LRRK2 G2019S mutation and Parkinson's disease: A clinical, neuropsychological and neuropsychiatric study in a large Italian sample. Parkinsonism Relat Disord, 12, 410-419.
26. Shanker V, Groves M, Heiman G, Palmese C, Saunders-Pullman R, Ozelius L, Raymond D, & Bressman S (2011) Mood and cognition in leucine-rich repeat kinase 2 G2019S Parkinson's disease. Mov Disord, 26, 1875-1880.
27. Yahalom G, Kaplan N, Vituri A, Cohen OS, Inzelberg R, Kozlova E, Korczyn AD, Rosset S, Friedman E, & Hassin-Baer S (2012) Dyskinesias in patients with Parkinson's disease: Effect of the leucine-rich repeat kinase 2 (LRRK2) G2019S mutation. Parkinsonism Relat Disord, 18, 1039-1041.
28. Kachergus J, Mata IF, Hulihan M, Taylor JP, Lincoln S, Aasly J, Gibson JM, Ross OA, Lynch T, Wiley J, Payami H, Nutt J, Maraganore DM, Czyzewski K, Styczynska M, Wszolek ZK, Farrer MJ, & Toft M (2005) Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: Evidence of a common founder across European populations. Am J Hum Genet, 76, 672-680.
29. San Luciano M, Lipton RB, Wang C, Katz M, Zimmerman ME, Sanders AE, Ozelius LJ, Bressman SB, & Saunders-Pullman R (2010) Clinical expression of LRRK2 G2019S mutations in the elderly. Mov Disord, 25, 2571-2576.
30. Thaler A, Mirelman A, Gurevich T, Simon E, Orr-Urtreger A, Marder K, Bressman S, & Giladi N (2012) Lower cognitive performance in healthy G2019S LRRK2 mutation carriers. Neurology, 79, 1027-1032.
31. Mirelman A, Gurevich T, Giladi N, Bar-Shira A, Orr-Urtreger A, & Hausdorff JM (2011) Gait alterations in healthy carriers of the LRRK2 G2019S mutation. Ann Neurol, 69, 193-197.
32. Ponsen MM, Stoffers D, Booij J, van Eck-Smit BL,Wolters Ec, & Berendse HW (2004) Idiopathic hyposmia as a preclinical sign of Parkinson's disease. Ann Neurol, 56, 173-181.
33. Katzenschlager R, & Lees AJ (2004) Olfaction and Parkinson's syndromes: Its role in differential diagnosis. Curr Opin Neurol, 17, 417-423.
34. Saunders-Pullman R, Stanley K, Wang C, San Luciano M, Shanker V, Hunt A, Severt L, Raymond D, Ozelius LJ, Lipton RB, & Bressman SB (2011) Olfactory dysfunction in LRRK2 G2019S mutation carriers. Neurology, 77, 319-324.
35. Silveira-Moriyama L, Munhoz RP, de JCM, Raskin S, Rogaeva E, de CAP, Bressan RA, Felicio AC, Barsottini OG, Andrade LA, Chien HF, Bonifati V, Barbosa ER, Teive HA, & Lees AJ (2010) Olfactory heterogeneity in LRRK2 related Parkinsonism. Mov Disord, 25, 2879-2883.
36. Ruiz-Martinez J, Gorostidi A, Goyenechea E, Alzualde A, Poza JJ, Rodriguez F, Bergareche A, Moreno F, Lopez de Munain A, & Marti Masso JF (2011) Olfactory deficits and cardiac 123I-MIBG in Parkinson's disease related to the LRRK2 R1441G and G2019S mutations. Mov Disord, 26, 2026-2031.
37. Sierra M, Sanchez-Juan P, Martinez-Rodriguez MI, Gonzalez-Aramburu I, Garcia-Gorostiaga I, Quirce MR, Palacio E, Carril JM, Berciano J, Combarros O, Infante J (2013) Olfaction and imaging biomarkers in premotor LRRK2 G2019S-associated Parkinson disease. Neurology, 80, 621-626.
38. Santpere G, & Ferrer I (2009) LRRK2 and neurodegeneration. Acta Neuropathol, 117, 227-246.
39. Wider C, Dickson DW, & Wszolek ZK (2010) Leucinerich repeat kinase 2 gene-associated disease: Redefining genotype-phenotype correlation. Neurodegener Dis, 7, 175-179.
40. Ruffmann C, Giaccone G, Canesi M, Bramerio M, Goldwurm S, Gambacorta M, Rossi G, Tagliavini F, & Pezzoli G (2012) Atypical tauopathy in a patient with LRRK2-G2019S mutation and tremor-dominant Parkinsonism. Neuropathol Appl Neurobiol, 38, 382-386.
41. Ujiie S, Hatano T, Kubo S, Imai S, Sato S, Uchihara T, Yagishita S, Hasegawa K, Kowa H, Sakai F, & Hattori N (2012) LRRK2 I2020T mutation is associated with tau pathology. Parkinsonism Relat Disord, 18, 819-823.
42. Khan NL, Jain S, Lynch JM, Pavese N, Abou-Sleiman P, Holton JL, Healy DG, Gilks WP, Sweeney MG, Ganguly M, Gibbons V, Gandhi S, Vaughan J, Eunson LH, Katzenschlager R, Gayton J, Lennox G, Revesz T, Nicholl D, Bhatia KP, Quinn N, Brooks D, Lees AJ, Davis MB, Piccini P, Singleton AB, & Wood NW (2005) Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease: Clinical, pathological, olfactory and functional imaging and genetic data. Brain, 128, 2786-2796.
43. Wszolek ZK, Vieregge P, Uitti RJ, Gasser T, Yasuhara O, McGeer P, Berry K, Calne DB, Vingerhoets FJ, Klein C, & Pfeiffer RF (1997) German-Canadian family (family A) with parkinsonism, amyotrophy, and dementia-Longitudinal observations. Parkinsonism Relat Disord, 3, 125-139.
44. Wszolek ZK, Pfeiffer RF, Tsuboi Y, Uitti RJ, McComb RD, Stoessl AJ, Strongosky AJ, Zimprich A, Muller-Myhsok B, Farrer MJ, Gasser T, Calne DB, & Dickson DW (2004) Autosomal dominant parkinsonism associated with variable synuclein and tau pathology. Neurology, 62, 1619-1622.
45. Marti-Masso JF, Ruiz-Martinez J, Bolano MJ, Ruiz I, Gorostidi A, Moreno F, Ferrer I, & Lopez de Munain A (2009) Neuropathology of Parkinson's disease with the R1441G mutation in LRRK2. Mov Disord, 24, 1998-2001.
46. Puschmann A, Englund E, Ross OA, Vilarino-Guell C, Lincoln SJ, Kachergus JM, Cobb SA, Tornqvist AL, Rehncrona S, Widner H, Wszolek ZK, Farrer MJ, & Nilsson C (2011) First neuropathological description of a patient with Parkinson's disease and LRRK2 p. N1437H mutation. Parkinsonism Relat Disord, 18, 332-338.
47. Simon-Sanchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, Berg D, Paisan-Ruiz C, Lichtner P, Scholz SW, Hernandez DG, Kruger R, Federoff M, Klein C, Goate A, Perlmutter J, Bonin M, Nalls MA, Illig T, Gieger C, Houlden H, Steffens M, Okun MS, Racette BA, Cookson MR, Foote KD, Fernandez HH, Traynor BJ, Schreiber S, Arepalli S, Zonozi R, Gwinn K, van der Brug M, Lopez G, Chanock SJ, Schatzkin A, Park Y, Hollenbeck A, Gao J, Huang X, Wood NW, Lorenz D, Deuschl G, Chen H, Riess O, Hardy JA, Singleton AB, & Gasser T (2009) Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat Genet, 41, 1308-1312.
48. Gan-Or Z, Bar-Shira A, Mirelman A, Gurevich T, Giladi N, & Orr-Urtreger A (2012) The age at motor symptoms onset in LRRK2-associated Parkinson's disease is affected by a variation in the MAPT locus: A possible interaction. J Mol Neurosci, 46, 541-544.
49. Golub Y, Berg D, Calne DB, Pfeiffer RF, Uitti RJ, Stoessl AJ, Wszolek ZK, Farrer MJ,Mueller JC, GasserT,&Fuchs J (2009) Genetic factors influencing age at onset in LRRK2-linked Parkinson disease. Parkinsonism Relat Disord, 15, 539-541.
50. Cardo LF, Coto E, de Mena L, Ribacoba R, Lorenzo-Betancor O, Pastor P, Samaranch L, Mata IF, Diaz M, Moris G, Menendez M, Corao AI,&AlvarezV(2012) Asearch for SNCA 3' UTR variants identified SNP rs356165 as a determinant of disease risk and onset age in Parkinson's disease. J Mol Neurosci, 47, 425-430.
51. Botta-Orfila T, Ezquerra M, Pastor P, Fernandez-Santiago R, Pont-Sunyer C, Compta Y, Lorenzo-Betancor O, Samaranch L, Marti MJ, Valldeoriola F, Calopa M, Fernandez M, Aguilar M, de Fabregas O, Hernandez-Vara J, & Tolosa E (2012) Age at onset in LRRK2-associated PD is modified by SNCA variants. J Mol Neurosci, 48, 245-247.
52. Biskup S, Mueller JC, Sharma M, Lichtner P, Zimprich A, Berg D, Ẅullner U, Illig T, Meitinger T, & Gasser T (2005) Common variants of LRRK2 are not associated with sporadic Parkinson's disease. Ann Neurol, 58, 905-908.
53. Paiśan-Rúz C, Lang AE, Kawarai T, Sato C, Salehi-Rad S, Fisman GK, Al-Khairallah T, St George-Hyslop P, Singleton A, & Rogaeva E (2005) LRRK2 gene in Parkinson disease: Mutation analysis and case control association study. Neurology, 65, 696-700.
54. Paiśan-Rúz C, EvansEW, Jain S, Xiromerisiou G, Gibbs JR, Eerola J, Gourbali V, Hellstr̈om O, Duckworth J, Papadimitriou A, Tienari PJ, Hadjigeorgiou GM, & Singleton AB (2006) Testing association between LRRK2 and Parkinson's disease and investigating linkage disequilibrium. J Med Genet, 43, e9.
55. Mata IF, Kachergus JM, Taylor JP, Lincoln S, Aasly J, Lynch T, Hulihan MM, Cobb SA, Wu R-M, Lu C-S, Lahoz C, Wszolek ZK, & Farrer MJ (2005) Lrrk2 pathogenic substitutions in Parkinson's disease. Neurogenetics, 6, 171-177.
56. Di Fonzo A, Wu-Chou Y-H, Lu C-S, van Doeselaar M, Simons EJ, Roh́e CF, Chang H-C, Chen R-S, Weng Y-H, Vanacore N, Breedveld GJ, Oostra BA, & Bonifati V (2006) A common missense variant in the LRRK2 gene, Gly2385Arg, associated with Parkinson's disease risk in Taiwan. Neurogenetics, 7, 133-138.
57. Tan EK, Zhao Y, Skipper L, Tan MG, Di Fonzo A, Sun L, Fook-Chong S, Tang S, Chua E, Yuen Y, Tan L, Pavanni R, Wong MC, Kolatkar P, Lu CS, Bonifati V, & Liu JJ (2007) The LRRK2 Gly2385Arg variant is associated with Parkinson's disease: Genetic and functional evidence. Hum Genet, 120, 857-863.
58. Fung H-C, Chen C-M, Hardy J, Singleton AB, & Wu Y-R (2006) A common genetic factor for Parkinson disease in ethnic Chinese population in Taiwan. BMC Neurol, 6, 47
59. Li C, Ting Z, Qin X, YingW, Li B, Guo Qiang L, Jian Fang M, Jing Z, Jian Qing D,&Sheng DiC(2007) The prevalence of LRRK2 Gly2385Arg variant in Chinese Han population with Parkinson's disease. Mov Disord, 22, 2439-2443.
60. Tan E-K, Zhao Y, Tan L, Lim H-Q, Lee J, Yuen Y, Pavanni R,Wong M-C, Fook-Chong S, & Liu J-J (2007) Analysis of LRRK2Gly2385Arg genetic variant in non-Chinese Asians. Mov Disord, 22, 1816-1818.
61. Funayama M, Li Y, Tomiyama H, Yoshino H, Imamichi Y, Yamamoto M, Murata M, Toda T, Mizuno Y, & Hattori N (2007) Leucine-rich repeat kinase 2 G2385R variant is a risk factor for Parkinson disease in Asian population. Neuroreport, 18, 273-275.
62. Chan DKY, Ng PW, Mok V, Yeung J, Fang ZM, Clarke R, Leung E, & Wong L (2008) LRRK2 Gly2385Arg mutation and clinical features in a Chinese population with earlyonset Parkinson's disease compared to late-onset patients. J Neural Transm, 115, 1275-1277.
63. Choi JM,WooMS, Ma H-I, Kang SY, Sung Y-H, Yong SW, Chung SJ, Kim J-S, Shin H, Lyoo CH, Lee PH, Baik JS, Kim S-J, Park MY, Sohn YH, Kim J-H, Kim JW, Lee MS, Lee MC, Kim D-H, & Kim YJ (2008) Analysis of PARK genes in a Korean cohort of early-onset Parkinson disease. Neurogenetics, 9, 263-269.
64. Zabetian CP, Yamamoto M, Lopez AN, Ujike H, Mata IF, Izumi Y, Kaji R, Maruyama H, Morino H, Oda M, Hutter CM, Edwards KL, Schellenberg GD, Tsuang DW, Yearout D, Larson EB,&KawakamiH(2009)LRRK2mutations and risk variants in Japanese patients with Parkinson's disease. Mov Disord, 24, 1034-1041.
65. Kim J-M, Lee J-Y, Kim HJ, Kim JS, Shin E-S, Cho J-H, Park SS, & Jeon BS (2010) The LRRK2 G2385R variant is a risk factor for sporadic Parkinson's disease in the Korean population. Parkinsonism Relat Disord, 16, 85-88.
66. Tan E-K, Peng R, Teo Y-Y, Tan LC, Angeles D, Ho P, Chen M-L, Lin C-H, Mao X-Y, Chang X-L, Prakash KM, Liu J-J, Au W-L, Le W-D, Jankovic J, Burgunder J-M, Zhao Y, & Wu R-M (2010) Multiple LRRK2 variants modulate risk of Parkinson disease:AChinese multicenter study.HumMutat, 31, 561-568.
67. Miyake Y, Tsuboi Y, Koyanagi M, Fujimoto T, Shirasawa S, Kiyohara C, Tanaka K, Fukushima W, Sasaki S, Yamada T, OedaT, MikiT, Kawamura N, Sakae N, Fukuyama H, Hirota Y, & Nagai M (2010) LRRK2 Gly2385Arg polymorphism, cigarette smoking, and risk of sporadic Parkinson's disease: A case-control study in Japan. J Neurol Sci, 297, 15-18.
68. Lin C-H, Wu R-M, Tai C-H, Chen M-L, & Hu F-C (2011) Lrrk2 S1647T and BDNF V66M interact with environmental factors to increase risk of Parkinson's disease. Parkinsonism Relat Disord, 17, 84-88.
69. Lill CM, Roehr JT, McQueen MB, Kavvoura FK, Bagade S, Schjeide B-MM, Schjeide LM, Meissner E, Zauft U, Allen NC, Liu T, Schilling M, Anderson KJ, Beecham G, Berg D, Biernacka JM, Brice A, Destefano AL, Do CB, Eriksson N, Factor SA, Farrer MJ, Foroud T, Gasser T, Hamza T, Hardy JA, Heutink P, Hill-BurnsEM,Klein C, Latourelle JC, Maraganore DM, Martin ER, Martinez M, Myers RH, Nalls MA, Pankratz N, Payami H, Satake W, Scott WK, Sharma M, Singleton AB, Stefansson K, Toda T, Tung JY, Vance J, Wood NW, Zabetian CP, Young P, Tanzi RE, Khoury MJ, Zipp F, Lehrach H, Ioannidis JPA, & Bertram L (2012) Comprehensive Research Synopsis and Systematic Meta-Analyses in Parkinson's Disease Genetics: The PDGene Database. PLoS Genetics, 8, e1002548.
70. RossOA,WuY-R, Lee M-C, Funayama M, Chen M-L, Soto AI, Mata IF, Lee-Chen G-J, Chen CM, Tang M, Zhao Y, Hattori N, Farrer MJ, Tan E-K, &Wu R-M (2008) Analysis of Lrrk2 R1628P as a risk factor for Parkinson's disease. Ann Neurol, 64, 88-92.
71. Tan E-K, Tang M, Tan LC, Wu Y-R, Wu R-M, Ross OA, & Zhao Y (2008) Lrrk2 R1628P in non-Chinese Asian races. Ann Neurol, 64, 472-473.
72. Lu C-S,Wu-ChouY-H, van Doeselaar M, Simons EJ, Chang H-C, Breedveld GJ, Di Fonzo A, Chen R-S, Weng Y-H, Lai S-C, Oostra BA, & Bonifati V (2008) The LRRK2 Arg1628Pro variant is a risk factor for Parkinson's disease in the Chinese population. Neurogenetics, 9, 271-276.
73. Zhang Z, Burgunder J-M, An X, Wu Y, Chen W, Zhang J, Wang Y, Xu Y, Gou Y, Yuan G, Mao X, & Peng R (2009) LRRK2 R1628P variant is a risk factor of Parkinson's disease among Han-Chinese from mainland China. Mov Disord, 24, 1902-1905.
74. Yu L, Hu F, Zou X, Jiang Y, Liu Y, He X, Xi J, Liu L, Liu Z, He L,&XuY(2009) LRRK2 R1628P contributes to Parkinson's disease susceptibility in Chinese Han populations from mainland China. Brain Res, 1296, 113-116.
75. Fu X, ZhengY, Hong H,HeY, Zhou S,GuoC, LiuY, XianW, Zeng J, Li J, Liu Z, Chen L,&Pei Z (2012) LRRK2 G2385R and LRRK2 R1628P increase risk of Parkinson's disease in a Han Chinese population from Southern Mainland China. Parkinsonism Relat Disord, 19, 397-398.
76. Pulkes T, Papsing C, Mahasirimongkol S, Busabaratana M, Kulkantrakorn K, & Tiamkao S (2011) Frequencies of LRRK2 variants in Thai patients with Parkinson's disease: Evidence for an R1628P founder. J Neurol Neurosurg Psychiatr, 82, 1179-1180.
77. Paiśan-Rúz C, Nath P,Washecka N, Gibbs JR, & Singleton AB (2008) Comprehensive analysis of LRRK2 in publicly available Parkinson's disease cases and neurologically normal controls. Hum Mutat, 29, 485-490.
78. Nuytemans K, Meeus B, Crosiers D, Brouwers N, Goossens D, Engelborghs S, Pals P, Pickut B, Van den Broeck M, Corsmit E, Cras P, De Deyn PP, Del-Favero J, Van Broeckhoven C, & Theuns J (2009) Relative contribution of simple mutations vs. copy number variations in five Parkinson disease genes in the Belgian population. Human Mutation, 30, 1054-1061.
79. Chung SJ, Armasu SM, Biernacka JM, Lesnick TG, Rider DN, Lincoln SJ, Ortolaza AI, Farrer MJ, Cunningham JM, Rocca WA, & Maraganore DM (2011) Common variants in PARK loci and related genes and Parkinson's disease. Movement Disorders, 26, 280-288.
80. Li N-N, Tan E-K, Chang X-L, Mao X-Y, Zhang J-H, Zhao D-M, Liao Q, & Peng R (2012) Genetic analysis of LRRK2 A419V variant in ethnic Chinese. Neurobiol Aging, 33, 1849.e1-3.
81. Wu YR, Tan LC, Fu X, Chen CM, Au WL, Chen L, Chen YC, Prakash KM, Zheng Y, Lee-Chen G-J, Zhao Y, Zeng JS, Tan EK, & Pei Z (2012) LRRK2 A419V is not associated with Parkinson's disease in different Chinese populations. PLoS ONE, 7, e36123.
82. Wu X, Tang K-F, Li Y, Xiong Y-Y, Shen L, Wei Z-Y, Zhou K-J, Niu J-M, Han X, Yang L, Feng G-Y, He L, & Qin S-Y (2012) Quantitative assessment of the effect of LRRK2 exonic variants on the risk of Parkinson's disease: A metaanalysis. Parkinsonism Relat Disord, 18, 722-730.
83. Wu-Chou Y-H, Chen Y-T, Yeh T-H, Chang H-C,Weng Y-H, Lai S-C, Huang C-L, Chen R-S, Huang Y-Z, Chen C-C, Hung J, ChuangW-L, LinW-Y, Chen C-H,&Lu C-S (2012) Genetic variants of SNCA and LRRK2 genes are associated with sporadic PD susceptibility: A replication study in a Taiwanese cohort. Parkinsonism Relat Disord, 19, 251-255.
84. Hindorff LA, Sethupathy P, Junkins HA, Ramos EM, Mehta JP, Collins FS,&Manolio TA (2009) Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci USA, 106, 9362-9367.
85. Satake W, Nakabayashi Y, Mizuta I, Hirota Y, Ito C, Kubo M, Kawaguchi T, Tsunoda T, Watanabe M, Takeda A, Tomiyama H, Nakashima K, Hasegawa K, Obata F, Yoshikawa T, Kawakami H, Sakoda S, Yamamoto M, Hattori N, Murata M, Nakamura Y, & Toda T (2009) Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease. Nat Genet, 41, 1303-1307.
86. Nalls MA, Plagnol V, Hernandez DG, Sharma M, Sheerin U-M, Saad M, Siḿon-Śanchez J, Schulte C, Lesage S, Sveinbj̈ornsd́ ottir S, Stef́ansson K, Martinez M, Hardy J, Heutink P, Brice A, Gasser T, Singleton AB, & Wood NW (2011) Imputation of sequence variants for identification of genetic risks for Parkinson's disease: A meta-analysis of genome-wide association studies. Lancet, 377, 641-649.
87. Sharma M, Ioannidis JPA, Aasly JO, Annesi G, Brice A,Van Broeckhoven C, Bertram L, Bozi M, Crosiers D, Clarke C, Facheris M, Farrer M, Garraux G, Gispert S, Auburger G, Vilariño-G̈uell C, Hadjigeorgiou GM, Hicks AA, Hattori N, Jeon B, Lesage S, LillCM,Lin J-J,LynchT, Lichtner P, Lang AE, Mok V, Jasinska-Myga B, Mellick GD, Morrison KE, Opala G, Pramstaller PP, Pichler I, Park SS, Quattrone A, Rogaeva E, RossOA, Stefanis L, Stockton JD, SatakeW, Silburn PA, Theuns J, Tan E-K, Toda T, Tomiyama H, Uitti RJ, Wirdefeldt K, Wszolek Z, Xiromerisiou G, Yueh K-C, Zhao Y, Gasser T, Maraganore D, & Kr̈uger R (2012) Large-scale replication and heterogeneity in Parkinson disease genetic loci. Neurology, 79, 659-667.
88. Gibbs JR, van der Brug MP, Hernandez DG, Traynor BJ, Nalls MA, Lai S-L, Arepalli S, Dillman A, Rafferty IP, Troncoso J, Johnson R, Zielke HR, Ferrucci L, Longo DL, Cookson MR, & Singleton AB (2010) Abundant Quantitative Trait Loci Exist for DNA Methylation and Gene Expression in Human Brain. PLoS Genet, 6, e1000952.
89. Singleton A, & Hardy J (2011) A generalizable hypothesis for the genetic architecture of disease: Pleomorphic risk loci. Human Molecular Genetics, 20, R158-R162.
90. Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J, Levey AI, Lah JJ, Rujescu D, Hampel H, Giegling I, Andreassen OA, Engedal K, Ulstein I, Djurovic S, Ibrahim-Verbaas C, Hofman A, Ikram MA, van Duijn CM, Thorsteinsdottir U,Kong A, & Stefansson K (2013) Variant of TREM2 associated with the risk of Alzheimer's disease. N Engl J Med, 368, 107-116.
91. Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C, Kauwe JSK, Younkin S, Hazrati L, Collinge J, Pocock J, Lashley T, Williams J, Lambert J-C, Amouyel P, Goate A, Rademakers R, Morgan K, Powell J, St George-Hyslop P, Singleton A, & Hardy J (2013) TREM2 variants in Alzheimer's disease. N Engl J Med, 368, 117-127.
92. Cookson MR (2010) The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease. Nat Rev Neurosci, 11, 791-797.
93. Bosgraaf L, & Van Haastert PJ (2003) Roc, a Ras/GTPase domain in complex proteins. Biochim Biophys Acta, 1643, 5-10.
94. Marin I (2006) The Parkinson disease gene LRRK2: Evolutionary and structural insights. Molecular Biology and Evolution, 23, 2423-2433.
95. Lewis PA (2009) The function of ROCO proteins in health and disease. Biol Cell, 101, 183-191.
96. Deng J, Lewis PA, Greggio E, Sluch E, Beilina A, & Cookson MR (2008) Structure of the ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase. Proc Natl Acad Sci USA, 105, 1499-1504.
97. Gotthardt K, Weyand M, Kortholt A, Van Haastert PJ, & Wittinghofer A (2008) Structure of the Roc-COR domain tandem of C. tepidum, a prokaryotic homologue of the human LRRK2 Parkinson kinase. EMBO J, 27, 2352.
98. Gilsbach BK, Ho FY, Vetter IR, van Haastert PJ, Wittinghofer A, & Kortholt A (2012) Roco kinase structures give insights into the mechanism of Parkinson diseaserelated leucine-rich-repeat kinase 2 mutations. Proc Natl Acad Sci USA, 109, 10322-10327.
99. Gasper R, Meyer S, Gotthardt K, Sirajuddin M, & Wittinghofer A (2009) It takes two to tango: Regulation of G proteins by dimerization. Nat Rev Mol Cell Biol, 10, 423-429.
100. Greggio E, Zambrano I, Kaganovich A, Beilina A, Taymans JM, Daniels V, Lewis P, Jain S, Ding J, Syed A, Thomas KJ, Baekelandt V, & Cookson MR (2008) The Parkinson disease-associated leucine-rich repeat kinase 2 (LRRK2) is a dimer that undergoes intramolecular autophosphorylation. J Biol Chem, 283, 16906-16914.
101. Sen S, Webber PJ, & West AB (2009) Dependence of leucine-rich repeat kinase 2 (LRRK2) kinase activity on dimerization. J Biol Chem, 284, 36346-36356.
102. Klein CL, Rovelli G, Springer W, Schall C, Gasser T, & Kahle PJ (2009) Homo-and heterodimerization of ROCO kinases: LRRK2 kinase inhibition by the LRRK2 ROCO fragment. J Neurochem, 111, 703-715.
103. Ito G, & Iwatsubo T (2012) Re-examination of the dimerization state of leucine-rich repeat kinase 2: Predominance of the monomeric form. Biochem J, 441, 987-994.
104. civiero L, Vancraenenbroeck R, Belluzzi E, Beilina A, Lobbestael E, Reyniers L, Gao F, Micetic I, De Maeyer M, Bubacco L, Baekelandt V, Cookson MR, Greggio E, & Taymans JM (2012) Biochemical characterization of highly purified leucine-rich repeat kinases 1 and 2 demonstrates formation of homodimers. PLoS One, 7, e43472.
105. James NG, Digman MA, Gratton E, Barylko B, Ding X, Albanesi JP, GoldbergMS, & Jameson DM (2012) Number and brightness analysis of LRRK2 oligomerization in live cells. Biophys J, 102, L41-L43.
106. West AB, Moore DJ, Biskup S, Bugayenko A, Smith WW, Ross CA, Dawson VL, & Dawson TM (2005) Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci USA, 102, 16842-16847.
107. Gloeckner CJ, Kinkl N, Schumacher A, Braun RJ, O'Neill E, Meitinger T, Kolch W, Prokisch H, & Ueffing M (2006) The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity. Human molecular genetics, 15, 223-232.
108. Greggio E, Jain S, Kingsbury A, Bandopadhyay R, Lewis P, Kaganovich A, van der Brug MP, Beilina A, Blackinton J, Thomas KJ, Ahmad R, Miller DW, Kesavapany S, Singleton A, Lees A, Harvey RJ, Harvey K, Cookson MR (2006) Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiol Dis, 23, 329-341.
109. Lewis PA, Greggio E, Beilina A, Jain S, Baker A,&Cookson MR (2007) The R1441C mutation of LRRK2 disrupts GTP hydrolysis. Biochemical and biophysical research communications, 357, 668-671.
110. Guo L, Gandhi PN,WangW, Petersen RB,Wilson-Delfosse AL, & Chen SG (2007) The Parkinson's disease-associated protein, leucine-rich repeat kinase 2 (LRRK2), is an authentic GTPase that stimulates kinase activity. Experimental cell research, 313, 3658-3670.
111. Li X, Tan YC, Poulose S, Olanow CW, Huang XY, & Yue Z (2007) Leucine-rich repeat kinase 2 (LRRK2)/PARK8 possesses GTPase activity that is altered in familial Parkinson's disease R1441C/G mutants. J Neurochem, 103, 238-247.
112. Korr D, Toschi L, Donner P, Pohlenz HD, Kreft B, &Weiss B (2006) LRRK1 protein kinase activity is stimulated upon binding of GTP to its Roc domain. Cell Signal, 18, 910-920.
113. Ito G, Okai T, Fujino G, Takeda K, Ichijo H, Katada T, & Iwatsubo T (2007) GTP Binding Is Essential to the Protein Kinase Activity of LRRK2, a Causative Gene Product for Familial Parkinson's Disease. Biochemistry, 46, 1380-1388.
114. West AB, Moore DJ, Choi C, Andrabi SA, Li X, Dikeman D, Biskup S, Zhang Z, Lim KL, Dawson VL,&DawsonTM (2007) Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Hum Mol Genet, 16, 223-232.
115. Smith WW, Pei Z, Jiang H, Dawson VL, Dawson TM, & Ross CA (2006) Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nature neuroscience, 9, 1231-1233.
116. Taymans JM, Vancraenenbroeck R, Ollikainen P, Beilina A, Lobbestael E, De Maeyer M, Baekelandt V, & Cookson MR (2011) LRRK2 Kinase Activity Is Dependent on LRRK2 GTP Binding Capacity but Independent of LRRK2 GTP Binding. PLoS One, 6, e23207
117. Greggio E, Taymans JM, Zhen EY, Ryder J, Vancraenenbroeck R, Beilina A,
118. Kamikawaji S, Ito G, & Iwatsubo T (2009) Identification of the autophosphorylation sites of LRRK2. Biochemistry, 48, 10963-10975.
119. Webber PJ, Smith AD, Sen S, Renfrow MB, Mobley JA, & West AB (2011) Autophosphorylation in the Leucine-Rich Repeat Kinase 2 (LRRK2)GTPase Domain Modifies Kinase and GTP-Binding Activities. J Mol Biol, 412, 94-110.
120. Jaleel M, Nichols RJ, Deak M, Campbell DG, Gillardon F, Knebel A, & Alessi DR (2007) LRRK2 phosphorylates moesin at threonine-558: Characterization of how Parkinson's disease mutants affect kinase activity. Biochem J, 405, 307-317.
121. Rudenko IN, Kaganovich A, Hauser DN, Beylina A, Chia R, Ding J, Maric D, Jaffe H, & Cookson MR (2012) The G2385R variant of leucine-rich repeat kinase 2 associated with Parkinson's disease is a partial loss-of-function mutation. Biochem J, 446, 99-111.
122. Berger Z, Smith KA, & Lavoie MJ (2010) Membrane localization of LRRK2 is associated with increased formation of the highly active LRRK2 dimer and changes in its phosphorylation. Biochemistry, 49, 5511-5523.
123. Lewis PA,&Manzoni C (2012) LRRK2 and human disease: A complicated question or a question of complexes? Sci Signal, 5, pe2.
124. Berwick DC, & Harvey K (2011) LRRK2 signaling pathways: The key to unlocking neurodegeneration? Trends Cell Biol, 21, 257-265.
125. Imai Y, Gehrke S, Wang HQ, Takahashi R, Hasegawa K, Oota E, & Lu B (2008) Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila. Embo J, 27, 2432-2443.
126. Dzamko N, Inesta-Vaquera F, Zhang J, Xie C, Cai H, Arthur S, Tan L, Choi H, Gray N, Cohen P, Pedrioli P, Clark K, & Alessi DR (2012) The IkappaB Kinase Family Phosphorylates the Parkinson's Disease Kinase LRRK2 at Ser935 and Ser910 during Toll-Like Receptor Signaling. PLoS One, 7, e39132.
127. Sancho RM, Law BM, & Harvey K (2009) Mutations in the LRRK2 Roc-COR tandem domain link Parkinson's disease to Wnt signalling pathways. Hum Mol Genet, 18, 3955-3968.
128. Bravo-San Pedro JM, Niso-Santano M, Gomez-Sanchez R, Pizarro-Estrella E, Aiastui-Pujana A, Gorostidi A, Climent V, Lopez de Maturana R, Sanchez-Pernaute R, Lopez de Munain A, Fuentes JM, & Gonzalez-Polo RA (2012) The LRRK2 G2019S mutant exacerbates basal autophagy through activation of the MEK/ERK pathway. Cell Mol Life Sci, 70, 121-136.
129. Nichols RJ, Dzamko N, Morrice NA, Campbell DG, Deak M, Ordureau A, Macartney T, Tong Y, Shen J, Prescott AR, & Alessi DR (2010) 14-3-3 binding to LRRK2 is disrupted by multiple Parkinson's disease-associated mutations and regulates cytoplasmic localization. Biochem J, 430, 393-404.
130. Li X, Wang QJ, Pan N, Lee S, Zhao Y, Chait BT, & Yue Z (2011) Phosphorylation-dependent 14-3-3 binding to LRRK2 is impaired by common mutations of familial Parkinson's disease. PLoS One, 6, e17153.
131. Dzamko N, Deak M, Hentati F, Reith AD, Prescott AR, Alessi DR,&Nichols RJ (2010) Inhibition ofLRRK2kinase activity leads to dephosphorylation of Ser(910)/Ser(935), disruption of 14-3-3 binding and altered cytoplasmic localization. Biochem J, 430, 405-413.
132. Biskup S, Moore DJ, Celsi F, Higashi S,West AB, Andrabi SA, Kurkinen K, Yu S-W, Savitt JM, Waldvogel HJ, Faull RLM, Emson PC, Torp R, Ottersen OP, Dawson TM, & Dawson VL (2006) Localization of LRRK2 to membranous and vesicular structures in mammalian brain. Ann Neurol, 60, 557-569.
133. Hatano T, Kubo S-I, Imai S, Maeda M, Ishikawa K, Mizuno Y, & Hattori N (2007) Leucine-rich repeat kinase 2 associates with lipid rafts. Hum Mol Genet, 16, 678-690.
134. Alegre-Abarrategui J, Christian H, LufinoMMP,Mutihac R, Venda LL, Ansorge O, & Wade-Martins R (2009) LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model. Hum Mol Genet, 18, 4022-4034.
135. Piccoli G, Condliffe SB, Bauer M, Giesert F, Boldt K, De Astis S, Meixner A, Sarioglu H, Vogt-Weisenhorn DM, Wurst W, Gloeckner CJ, Matteoli M, Sala C, & Ueffing M (2011) LRRK2 controls synaptic vesicle storage and mobilization within the recycling pool. J Neurosci, 31, 2225-2237.
136. Matta S, Van Kolen K, da Cunha R, van den Bogaart G, Mandemakers W, Miskiewicz K, De Bock P-J, Morais VA, Vilain S, Haddad D, Delbroek L, Swerts J, Ch́avez-Gutíerrez L, Esposito G, Daneels G, Karran E, Holt M, Gevaert K, Moechars DW, De Strooper B, & Verstreken P (2012) LRRK2 controls an EndoA phosphorylation cycle in synaptic endocytosis. Neuron, 75, 1008-1021.
137. Alegre-Abarrategui J, Ansorge O, Esiri M,&Wade-Martins R (2008) LRRK2 is a component of granular alphasynuclein pathology in the brainstem of Parkinson's disease. Neuropathol Appl Neurobiol, 34, 272-283.
138. Ǵomez-Suaga P, Luźon-Toro B, Churamani D, Zhang L, Bloor-Young D, Patel S, Woodman PG, Churchill GC, & Hilfiker S (2012) Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP. Hum Mol Genet, 21, 511-525.
139. Śanchez-Dańes A, Richaud-Patin Y, Carballo-Carbajal I, Jiḿenez-Delgado S, Caig C, Mora S, Di Guglielmo C, EzquerraM,Patel B, Giralt A, Canals JM,MemoM,Alberch J, Ĺopez-Barneo J, Vila M, Cuervo AM, Tolosa E, Consiglio A, & Raya A (2012) Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease. EMBO Mol Med, 4, 380-395.
140. Tong Y, Yamaguchi H, Giaime E, Boyle S, Kopan R, Kelleher RJ 3rd, & Shen J (2010) Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of alpha-synuclein, and apoptotic cell death in aged mice. Proc Natl Acad Sci USA, 107, 9879-9884.
141. Herzig MC, Kolly C, Persohn E, Theil D, Schweizer T, Hafner T, Stemmelen C, Troxler TJ, Schmid P, Danner S, Schnell CR, Mueller M, Kinzel B, Grevot A, Bolognani F, Stirn M, Kuhn RR, Kaupmann K, van der Putten PH, Rovelli G, & Shimshek DR (2011) LRRK2 protein levels are determined by kinase function and are crucial for kidney and lung homeostasis in mice. Hum Mol Genet, 20, 4209-4223.
142. Orenstein SJ, Kuo S-H, Tasset I, Arias E, Koga H, Fernandez-Carasa I, Cortes E, Honig LS, Dauer W, Consiglio A, Raya A, Sulzer D, & Cuervo AM (2013) Interplay of LRRK2 with chaperone-mediated autophagy. Nat Neurosci, 16, 394-406.
143. Macleod DA, Rhinn H, Kuwahara T, Zolin A, Di Paolo G, Maccabe BD, Marder KS, Honig LS, Clark LN, Small SA, & Abeliovich A (2013) RAB7L1 Interacts with LRRK2 to Modify Intraneuronal Protein Sorting and Parkinson's Disease Risk. Neuron, 77, 425-439.
144. Gehrke S, Imai Y, Sokol N, & Lu B (2010) Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression. Nature, 466, 637-41.
145. Cho HJ, Liu G, Jin SM, Parisiadou L, Xie C, Yu J, Sun L, Ma B, Ding J, Vancraenenbroeck R, Lobbestael E, Baekelandt V, Taymans J-M, He P, Troncoso JC, Shen Y, Cai H (2013) MicroRNA-205 regulates the expression of Parkinson's disease-related leucine-rich repeat kinase 2 protein. Hum Mol Genet, 22, 608-620.
146. Gandhi PN, Wang X, Zhu X, Chen SG, & Wilson-Delfosse AL (2008) The Roc domain of leucine-rich repeat kinase 2 is sufficient for interaction with microtubules. J Neurosci Res, 86, 1711-1720.
147. Gillardon F (2009) Leucine-rich repeat kinase 2 phosphorylates brain tubulin-beta isoforms and modulates microtubule stability-a point of convergence in parkinsonian neurodegeneration? J Neurochem, 110, 1514-1522.
148. Meixner A, Boldt K, Van Troys M, Askenazi M, Gloeckner CJ, Bauer M, Marto JA, Ampe C, Kinkl N, & Ueffing M (2011) A QUICK screen for Lrrk2 interaction partners-leucine-rich repeat kinase 2 is involved in actin cytoskeleton dynamics. Mol Cell Proteomics, 10, M110.001172.
149. Chan D, Citro A, Cordy JM, Shen GC, &Wolozin B (2011) Rac1 protein rescues neurite retraction caused by G2019S leucine-rich repeat kinase 2 (LRRK2). J Biol Chem, 286, 16140-16149.
150. Parisiadou L, Xie C, Cho HJ, Lin X, Gu X-L, Long C-X, Lobbestael E, Baekelandt V, Taymans J-M, Sun L, & Cai H (2009) Phosphorylation of ezrin/radixin/moesin proteins by LRRK2 promotes the rearrangement of actin cytoskeleton in neuronal morphogenesis. J Neurosci, 29, 13971-13980.
151. Gardet A, Benita Y, Li C, Sands BE, Ballester I, Stevens C, Korzenik JR, Rioux JD, Daly MJ, Xavier RJ, & Podolsky DK (2010) LRRK2 is involved in the IFN-gamma response and host response to pathogens. J Immunol, 185, 5577-5585.
152. Hakimi M, Selvanantham T, Swinton E, Padmore RF, Tong Y, Kabbach G, Venderova K, Girardin SE, Bulman DE, Scherzer CR, LaVoie MJ, Gris D, Park DS, Angel JB, Shen J, Philpott DJ, & Schlossmacher MG (2011) Parkinson's disease-linked LRRK2 is expressed in circulating and tissue immune cells and upregulated following recognition of microbial structures. J Neural Transm 118, 795-808.
153. Zhang F-R, Huang W, Chen S-M, Sun L-D, Liu H, Li Y, Cui Y, Yan X-X, Yang H-T, Yang R-D, Chu T-S, Zhang C, Zhang L, Han J-W, Yu G-Q, Quan C, Yu Y-X, Zhang Z, Shi B-Q, Zhang L-H, Cheng H, Wang C-Y, Lin Y, Zheng H-F, Fu X-A, Zuo X-B, Wang Q, Long H, Sun Y-P, Cheng Y-L, Tian H-Q, Zhou F-S, Liu H-X, Lu W-S, He S-M, Du W-L, Shen M, Jin Q-Y, Wang Y, Low H-Q, Erwin T, Yang N-H, Li J-Y, Zhao X, Jiao Y-L, Mao L-G, Yin G, Jiang Z-X,Wang X-D, Yu J-P, Hu Z-H, Gong C-H, Liu Y-Q, Liu R-Y, Wang D-M, Wei D, Liu J-X, Cao W-K, Cao H-Z, Li Y-P, Yan WG, Wei S-Y,Wang K-J, Hibberd ML, Yang S, Zhang X-J, & Liu J-J (2009) Genomewide association study of leprosy. N Engl J Med, 361, 2609-2618.
154. Franke A, McGovern DPB, Barrett JC, Wang K, Radford-Smith GL, Ahmad T, Lees CW, Balschun T, Lee J, Roberts R, Anderson CA, Bis JC, Bumpstead S, Ellinghaus D, Festen EM, Georges M, Green T, Haritunians T, Jostins L, Latiano A, Mathew CG, Montgomery GW, Prescott NJ, Raychaudhuri S, Rotter JI, Schumm P, Sharma Y, Simms LA, Taylor KD, Whiteman D, Wijmenga C, Baldassano RN, Barclay M, Bayless TM, Brand S, B̈uning C, Cohen A, Colombel J-F, Cottone M, Stronati L, Denson T, De Vos M, D'Inca R, Dubinsky M, Edwards C, Florin T, Franchimont D, Gearry R, Glas J, Van Gossum A, Guthery SL, Halfvarson J, VerspagetHW, Hugot J-P, Karban A, Laukens D, Lawrance I, Lemann M, Levine A, Libioulle C, Louis E, Mowat C, Newman W, Pańes J, Phillips A, Proctor DD, Regueiro M, Russell R, Rutgeerts P, Sanderson J, Sans M, Seibold F, Steinhart AH, Stokkers PCF, Torkvist L, Kullak-Ublick G,Wilson D,Walters T, Targan SR, Brant SR, Rioux JD, D'Amato M, Weersma RK, Kugathasan S, Griffiths AM, Mansfield JC, Vermeire S, Duerr RH, Silverberg MS, Satsangi J, Schreiber S, Cho JH, Annese V, Hakonarson H, Daly MJ, & Parkes M (2010) Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet, 42, 1118-1125.
155. Moehle MS, Webber PJ, Tse T, Sukar N, Standaert DG, DeSilva TM, Cowell RM, & West AB (2012) LRRK2 inhibition attenuates microglial inflammatory responses. J Neurosci, 32, 1602-1611.
156. Marker DF, Puccini JM, Mockus TE, Barbieri J, Lu S-M, & Gelbard HA (2012) LRRK2 kinase inhibition prevents pathological microglial phagocytosis in response to HIV-1 Tat protein. J Neuroinflammation, 9, 261.
157. Liu M, Kang S, Ray S, Jackson J, Zaitsev AD, Gerber SA, Cuny GD, & Glicksman MA (2011) Kinetic, mechanistic, and structural modeling studies of truncated wild-type leucine-rich repeat kinase 2 and the G2019S mutant. Biochemistry, 50, 9399-9408.
158. Greggio E, & Cookson MR (2009) Leucine Rich Repeat Kinase 2 mutations and Parkinson's disease: Three Questions. ASN Neuro, 1, e00002.
159. Li Y, Dunn L, Greggio E, Krumm B, Jackson GS, Cookson MR, Lewis PA, & Deng J (2009) The R1441C mutation alters the folding properties of the ROC domain of LRRK2. Biochim Biophys Acta, 1792, 1194-1197.
160. Ohta E, Katayama Y, Kawakami F, Yamamoto M, Tajima K, Maekawa T, Iida N, Hattori S, & Obata F (2009) I(2020)T leucine-rich repeat kinase 2, the causative mutant molecule of familial Parkinson's disease, has a higher intracellular degradation rate than the wild-type molecule. Biochem Biophys Res Commun, 390, 710-715.
161. Ho CC, Rideout HJ, Ribe E, Troy CM, & Dauer WT (2009) The Parkinson disease protein leucine-rich repeat kinase 2 transduces death signals via Fas-associated protein with death domain and caspase-8 in a cellular model of neurodegeneration. J Neurosci, 29, 1011-1016.
162. Ren G, Xin S, Li S, Zhong H, & Lin S (2011) Disruption of LRRK2 does not cause specific loss of dopaminergic neurons in zebrafish. PLoS ONE 6, e20630.
163. Sheng D, Qu D, Kwok KHH, Ng SS, Lim AYM, Aw SS, Lee CWH, Sung WK, Tan EK, Lufkin T, Jesuthasan S, Sinnakaruppan M, & Liu J (2010) Deletion of the WD40 domain of LRRK2 in Zebrafish causes Parkinsonism-like loss of neurons and locomotive defect. PLoS Genet, 6, e1000914.
164. Yao C, Johnson WM, Gao Y, Wang W, Zhang J, Deak M, Alessi DR, Zhu X, Mieyal JJ, Roder H,Wilson-Delfosse AL, & Chen SG (2013) Kinase inhibitors arrest neurodegeneration in cell and C. elegans models of LRRK2 toxicity. Hum Mol Genet, 22, 328-344.
165. Yuan Y, Cao P, Smith MA, Kramp K, Huang Y, Hisamoto N, Matsumoto K, Hatzoglou M, Jin H, & Feng Z (2011) Dysregulated LRRK2 signaling in response to endoplasmic reticulum stress leads to dopaminergic neuron degeneration in C. elegans. PLoS ONE, 6, e22354.
166. Sakaguchi-Nakashima A, Meir JY, Jin Y, Matsumoto K, & Hisamoto N (2007) LRK-1, a C. elegans PARK8-related kinase, regulates axonal-dendritic polarity of SV proteins. Curr Biol, 17, 592-598.
167. Lee SB, Kim W, Lee S, & Chung J (2007) Loss of LRRK2/PARK8induces degeneration of dopaminergic neurons in Drosophila. Biochem Biophys Res Commun, 358, 534-539.
168. Liu Z,Wang X, Yu Y, Li X,Wang T, Jiang H, Ren Q, Jiao Y, Sawa A, MoranT, Ross CA, Montell C,&SmithWW(2008) A Drosophila model for LRRK2-linked parkinsonism. Proc Natl Acad Sci USA, 105, 2693-2698.
169. Maŕn I (2008) Ancient origin of the Parkinson disease gene LRRK2. J Mol Evol, 67, 41-50.
170. Xu Q, Shenoy S, & Li C (2012) Mouse models for LRRK2 Parkinson's disease. Parkinsonism Relat Disord, 18(Suppl 1), S186-S189.
171. Beal MF (2010) Parkinson's disease: A model dilemma. Nature, 466, S8-S10.
172. Li Y, Liu W, Oo TF, Wang L, Tang Y, Jackson-Lewis V, Zhou C, Geghman K, BogdanovM, Przedborski S, BealMF, Burke RE, & Li C (2009) Mutant LRRK2(R1441G) BAC transgenic mice recapitulate cardinal features of Parkinson's disease. Nat Neurosci, 12, 826-828.
173. Lin X, Parisiadou L, Gu X-L, Wang L, Shim H, Sun L, Xie C, Long C-X, Yang W-J, Ding J, Chen ZZ, Gallant PE, Tao-Cheng J-H, Rudow G, Troncoso JC, Liu Z, Li Z, & Cai H (2009) Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant alpha-synuclein. Neuron, 64, 807-827.
174. Melrose HL, D̈achsel JC, Behrouz B, Lincoln SJ, Yue M, Hinkle KM, Kent CB, Korvatska E, Taylor JP, Witten L, Liang Y-Q, Beevers JE, Boules M, Dugger BN, Serna VA, Gaukhman A, Yu X, Castanedes-Casey M, Braithwaite AT, Ogholikhan S, Yu N, Bass D, Tyndall G, Schellenberg GD, Dickson DW, Janus C, & Farrer MJ (2010) Impaired dopaminergic neurotransmission and microtubule-associated protein tau alterations in human LRRK2 transgenic mice. Neurobiol Dis, 40, 503-517.
175. MacLeod D, Dowman J, Hammond R, Leete T, Inoue K, & Abeliovich A (2006) The familial Parkinsonism gene LRRK2 regulates neurite process morphology. Neuron, 52, 587-593.
176. Tong Y, Pisani A, Martella G, Karouani M, Yamaguchi H, Pothos EN, & Shen J (2009) R1441C mutation in LRRK2 impairs dopaminergic neurotransmission in mice. Proc Natl Acad Sci USA, 106, 14622-14627.
177. Lee BD, Shin J-H, VanKampen J, Petrucelli L,West AB, Ko HS, Lee Y-I, Maguire-Zeiss KA, Bowers WJ, Federoff HJ, Dawson VL, & Dawson TM (2010) Inhibitors of leucinerich repeat kinase-2 protect against models of Parkinson's disease. Nat Med, 16, 998-1000.
178. Dusonchet J, Kochubey O, Stafa K, Young SM Jr, Zufferey R, Moore DJ, Schneider BL, & Aebischer P (2011) A rat model of progressive nigral neurodegeneration induced by the Parkinson's disease-associated G2019S mutation in LRRK2. J Neurosci, 31, 907-912.
179. Liu Z, Lee J, Krummey S, Lu W, Cai H, & Lenardo MJ (2011) The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease. Nat Immunol, 12, 1063-1070.
180. Deng X, Dzamko N, Prescott A, Davies P, Liu Q, Yang Q, Lee JD, Patricelli MP, Nomanbhoy TK, Alessi DR, & Gray NS (2011) Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2. Nat Chem Biol, 7, 203-205.