Skip to main content
SpringerLink
Log in

The Neurobiology of LRRK2 and its Role in the Pathogenesis of Parkinson’s Disease

  • Overview
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Leucine-rich repeat kinase 2 (LRRK2) is a large, widely expressed protein of largely unknown function. Mutations in the gene encoding LRRK2 have been linked to multiple diseases, including a prominent association with familial and sporadic Parkinson’s disease (PD), as well as inflammatory bowel disorders such as Crohn’s disease. The LRRK2 protein possesses both kinase and GTPase signaling domains, as well as multiple protein interaction domains. Experimental studies in both cellular and in vivo models of mutant LRRK2-induced neurodegeneration have given clues to potential function(s) of LRRK2, yet much remains unknown. For example, while it is known that intact kinase and GTPase activity are required for mutant forms of the protein to trigger cell death, the specific targets of these enzymatic activities that mediate the death of neurons are not known. In this review, we discuss the evidence linking LRRK2 to various cellular/neuronal activities such as extrinsic death and inflammatory signaling, lysosomal protein degradation, the cytoskeletal system and neurite outgrowth, vesicle trafficking, mitochondrial dysfunction, as well as multiple points of interaction with several other genes linked to the pathogenesis of PD. In order for more effective therapeutic strategies to be envisioned and implemented, the mechanisms underlying LRRK2-mediated neurodegeneration need to be better characterized. Furthermore, insights into LRRK2-associated PD pathogenesis can potentially advance our understanding of the more common sporadic forms of PD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. de Rijk MC, Launer LJ, Berger K, Breteler MM, Dartigues JF, Baldereschi M, Fratiglioni L, Lobo A, Martinez-Lage J, Trenkwalder C, Hofman A (2000) Prevalence of Parkinson’s disease in Europe: a collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology 54(11 Suppl 5):S21–S23

    PubMed  Google Scholar 

  2. Lesage S, Brice A (2012) Role of mendelian genes in “sporadic” Parkinson’s disease. Parkinsonism Relat Disord 18(Suppl 1):S66–S70. doi:10.1016/S1353-8020(11)70022-0

    PubMed  Google Scholar 

  3. Funayama M, Hasegawa K, Kowa H, Saito M, Tsuji S, Obata F (2002) A new locus for Parkinson’s disease (PARK8) maps to chromosome 12p11.2-q13.1. Ann Neurol 51(3):296–301. doi:10.1002/ana.10113

    CAS  PubMed  Google Scholar 

  4. Paisan-Ruiz C, Jain S, Evans EW, Gilks WP, Simon J, van der Brug M, Lopez de Munain A, Aparicio S, Gil AM, Khan N, Johnson J, Martinez JR, Nicholl D, Carrera IM, Pena AS, de Silva R, Lees A, Marti-Masso JF, Perez-Tur J, Wood NW, Singleton AB (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron 44(4):595–600. doi:10.1016/j.neuron.2004.10.023

    CAS  PubMed  Google Scholar 

  5. 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(4):601–607. doi:10.1016/j.neuron.2004.11.005

    CAS  PubMed  Google Scholar 

  6. 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(6):918–921. doi:10.1002/ana.20484

    CAS  PubMed  Google Scholar 

  7. 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(4):672–680. doi:10.1086/429256

    CAS  PubMed Central  PubMed  Google Scholar 

  8. Di Fonzo A, Wu-Chou YH, Lu CS, van Doeselaar M, Simons EJ, Rohe CF, Chang HC, Chen RS, Weng YH, 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(3):133–138

    PubMed  Google Scholar 

  9. Spanaki C, Latsoudis H, Plaitakis A (2006) LRRK2 mutations on Crete: R1441H associated with PD evolving to PSP. Neurology 67(8):1518–1519. doi:10.1212/01.wnl.0000239829.33936.73

    PubMed  Google Scholar 

  10. Giordana MT, D’Agostino C, Albani G, Mauro A, Di Fonzo A, Antonini A, Bonifati V (2007) Neuropathology of Parkinson’s disease associated with the LRRK2 Ile1371Val mutation. Mov Disord 22(2):275–278. doi:10.1002/mds.21281

    PubMed  Google Scholar 

  11. 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(7):819–823. doi:10.1016/j.parkreldis.2012.03.024

    PubMed  Google Scholar 

  12. Marin I (2006) The Parkinson disease gene LRRK2: evolutionary and structural insights. Mol Biol Evol 23(12):2423–2433. doi:10.1093/molbev/msl114

    CAS  PubMed  Google Scholar 

  13. Marin I, van Egmond WN, van Haastert PJ (2008) The Roco protein family: a functional perspective. FASEB J 22(9):3103–3110. doi:10.1096/fj.08-111310

    CAS  PubMed  Google Scholar 

  14. 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(2):329–341

    CAS  PubMed  Google Scholar 

  15. Smith WW, Pei Z, Jiang H, Dawson VL, Dawson TM, Ross CA (2006) Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nat Neurosci 9(10):1231–1233. doi:10.1038/nn1776

    CAS  PubMed  Google Scholar 

  16. Meylan E, Tschopp J (2005) The RIP kinases: crucial integrators of cellular stress. Trends Biochem Sci 30(3):151–159. doi:10.1016/j.tibs.2005.01.003

    CAS  PubMed  Google Scholar 

  17. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr RH, Achkar JP, Brant SR, Bayless TM, Kirschner BS, Hanauer SB, Nunez G, Cho JH (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411(6837):603–606. doi:10.1038/35079114

    CAS  PubMed  Google Scholar 

  18. Kobayashi K, Inohara N, Hernandez LD, Galan JE, Nunez G, Janeway CA, Medzhitov R, Flavell RA (2002) RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems. Nature 416(6877):194–199. doi:10.1038/416194a

    CAS  PubMed  Google Scholar 

  19. Meylan E, Martinon F, Thome M, Gschwendt M, Tschopp J (2002) RIP4 (DIK/PKK), a novel member of the RIP kinase family, activates NF-kappa B and is processed during apoptosis. EMBO Rep 3(12):1201–1208. doi:10.1093/embo-reports/kvf236

    CAS  PubMed Central  PubMed  Google Scholar 

  20. 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(4):1011–1016. doi:10.1523/JNEUROSCI.5175-08.2009

    CAS  PubMed Central  PubMed  Google Scholar 

  21. Galter D, Westerlund M, Carmine A, Lindqvist E, Sydow O, Olson L (2006) LRRK2 expression linked to dopamine-innervated areas. Ann Neurol 59(4):714–719. doi:10.1002/ana.20808

    CAS  PubMed  Google Scholar 

  22. Higashi S, Moore DJ, Colebrooke RE, Biskup S, Dawson VL, Arai H, Dawson TM, Emson PC (2007) Expression and localization of Parkinson’s disease-associated leucine-rich repeat kinase 2 in the mouse brain. J Neurochem 100(2):368–381. doi:10.1111/j.1471-4159.2006.04246.x

    CAS  PubMed  Google Scholar 

  23. Westerlund M, Belin AC, Anvret A, Bickford P, Olson L, Galter D (2008) Developmental regulation of leucine-rich repeat kinase 1 and 2 expression in the brain and other rodent and human organs: implications for Parkinson’s disease. Neuroscience 152(2):429–436. doi:10.1016/j.neuroscience.2007.10.062

    CAS  PubMed  Google Scholar 

  24. Melrose H, Lincoln S, Tyndall G, Dickson D, Farrer M (2006) Anatomical localization of leucine-rich repeat kinase 2 in mouse brain. Neuroscience 139(3):791–794. doi:10.1016/j.neuroscience.2006.01.017

    CAS  PubMed  Google Scholar 

  25. 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(46):16842–16847. doi:10.1073/pnas.0507360102

    CAS  PubMed  Google Scholar 

  26. 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(1):238–247. doi:10.1111/j.1471-4159.2007.04743.x

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Sheng Z, Zhang S, Bustos D, Kleinheinz T, Le Pichon CE, Dominguez SL, Solanoy HO, Drummond J, Zhang X, Ding X, Cai F, Song Q, Li X, Yue Z, van der Brug MP, Burdick DJ, Gunzner-Toste J, Chen H, Liu X, Estrada AA, Sweeney ZK, Scearce-Levie K, Moffat JG, Kirkpatrick DS, Zhu H (2012) Ser1292 autophosphorylation is an indicator of LRRK2 kinase activity and contributes to the cellular effects of PD mutations. Sci Transl Med 4(164):164ra161. doi:10.1126/scitranslmed.3004485

    PubMed  Google Scholar 

  28. Gloeckner CJ, Boldt K, von Zweydorf F, Helm S, Wiesent L, Sarioglu H, Ueffing M (2010) Phosphopeptide analysis reveals two discrete clusters of phosphorylation in the N-terminus and the Roc domain of the Parkinson-disease associated protein kinase LRRK2. J Proteome Res 9(4):1738–1745. doi:10.1021/pr9008578

    CAS  PubMed  Google Scholar 

  29. Greggio E, Taymans JM, Zhen EY, Ryder J, Vancraenenbroeck R, Beilina A, Sun P, Deng J, Jaffe H, Baekelandt V, Merchant K, Cookson MR (2009) The Parkinson’s disease kinase LRRK2 autophosphorylates its GTPase domain at multiple sites. Biochem Biophys Res Commun 389(3):449–454

    CAS  PubMed Central  PubMed  Google Scholar 

  30. 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(1):94–110

    CAS  PubMed Central  PubMed  Google Scholar 

  31. Greggio E, Cookson MR (2009) Leucine-rich repeat kinase 2 mutations and Parkinson’s disease: three questions. ASN Neuro 1(1):e00002

    PubMed Central  PubMed  Google Scholar 

  32. Smith WW, Pei Z, Jiang H, Moore DJ, Liang Y, West AB, Dawson VL, Dawson TM, Ross CA (2005) Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Proc Natl Acad Sci USA 102(51):18676–18681. doi:10.1073/pnas.0508052102

    CAS  PubMed  Google Scholar 

  33. Kett LR, Boassa D, Ho CC, Rideout HJ, Hu J, Terada M, Ellisman M, Dauer WT (2012) LRRK2 Parkinson disease mutations enhance its microtubule association. Hum Mol Genet 21(4):890–899. doi:10.1093/hmg/ddr526

    CAS  PubMed  Google Scholar 

  34. 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(2):307–317. doi:10.1042/BJ20070209

    CAS  PubMed  Google Scholar 

  35. Parisiadou L, Xie C, Cho HJ, Lin X, Gu XL, Long CX, Lobbestael E, Baekelandt V, Taymans JM, 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(44):13971–13980. doi:10.1523/JNEUROSCI.3799-09.2009

    CAS  PubMed Central  PubMed  Google Scholar 

  36. 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(5):1514–1522. doi:10.1111/j.1471-4159.2009.06235.x

    CAS  PubMed  Google Scholar 

  37. Kawakami F, Yabata T, Ohta E, Maekawa T, Shimada N, Suzuki M, Maruyama H, Ichikawa T, Obata F (2012) LRRK2 phosphorylates tubulin-associated tau but not the free molecule: LRRK2-mediated regulation of the tau-tubulin association and neurite outgrowth. PLoS ONE 7(1):e30834. doi:10.1371/journal.pone.0030834

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Li Y, Liu W, Oo TF, Wang L, Tang Y, Jackson-Lewis V, Zhou C, Geghman K, Bogdanov M, Przedborski S, Beal MF, Burke RE, Li C (2009) Mutant LRRK2(R1441G) BAC transgenic mice recapitulate cardinal features of Parkinson’s disease. Nat Neurosci 12(7):826–828. doi:10.1038/nn.2349

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Ramonet D, Daher JP, Lin BM, Stafa K, Kim J, Banerjee R, Westerlund M, Pletnikova O, Glauser L, Yang L, Liu Y, Swing DA, Beal MF, Troncoso JC, McCaffery JM, Jenkins NA, Copeland NG, Galter D, Thomas B, Lee MK, Dawson TM, Dawson VL, Moore DJ (2011) Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2. PLoS ONE 6(4):e18568. doi:10.1371/journal.pone.0018568

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Plowey ED, Cherra SJ 3rd, Liu YJ, Chu CT (2008) Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells. J Neurochem 105(3):1048–1056. doi:10.1111/j.1471-4159.2008.05217.x

    CAS  PubMed Central  PubMed  Google Scholar 

  41. Maldonado H, Ramirez E, Utreras E, Pando ME, Kettlun AM, Chiong M, Kulkarni AB, Collados L, Puente J, Cartier L, Valenzuela MA (2011) Inhibition of cyclin-dependent kinase 5 but not of glycogen synthase kinase 3-beta prevents neurite retraction and tau hyperphosphorylation caused by secretable products of human T-cell leukemia virus type I-infected lymphocytes. J Neurosci Res 89(9):1489–1498. doi:10.1002/jnr.22678

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Winner B, Melrose HL, Zhao C, Hinkle KM, Yue M, Kent C, Braithwaite AT, Ogholikhan S, Aigner R, Winkler J, Farrer MJ, Gage FH (2011) Adult neurogenesis and neurite outgrowth are impaired in LRRK2 G2019S mice. Neurobiol Dis 41(3):706–716. doi:10.1016/j.nbd.2010.12.008

    CAS  PubMed Central  PubMed  Google Scholar 

  43. 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(18):2432–2443. doi:10.1038/emboj.2008.163

    CAS  PubMed  Google Scholar 

  44. Kumar A, Greggio E, Beilina A, Kaganovich A, Chan D, Taymans JM, Wolozin B, Cookson MR (2010) The Parkinson’s disease associated LRRK2 exhibits weaker in vitro phosphorylation of 4E-BP compared to autophosphorylation. PLoS ONE 5(1):e8730. doi:10.1371/journal.pone.0008730

    PubMed Central  PubMed  Google Scholar 

  45. Trancikova A, Mamais A, Webber PJ, Stafa K, Tsika E, Glauser L, West AB, Bandopadhyay R, Moore DJ (2012) Phosphorylation of 4E-BP1 in the Mammalian Brain Is Not Altered by LRRK2 expression or pathogenic mutations. PLoS ONE 7(10):e47784. doi:10.1371/journal.pone.0047784

    CAS  PubMed Central  PubMed  Google Scholar 

  46. Kanao T, Venderova K, Park DS, Unterman T, Lu B, Imai Y (2010) Activation of FoxO by LRRK2 induces expression of proapoptotic proteins and alters survival of postmitotic dopaminergic neuron in Drosophila. Hum Mol Genet 19(19):3747–3758. doi:10.1093/hmg/ddq289

    CAS  PubMed  Google Scholar 

  47. Park SJ, Sohn HY, Yoon J, Park SI (2009) Down-regulation of FoxO-dependent c-FLIP expression mediates TRAIL-induced apoptosis in activated hepatic stellate cells. Cell Signal 21(10):1495–1503. doi:10.1016/j.cellsig.2009.05.008

    CAS  PubMed  Google Scholar 

  48. Chen CY, Weng YH, Chien KY, Lin KJ, Yeh TH, Cheng YP, Lu CS, Wang HL (2012) (G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD. Cell Death Differ 19(10):1623–1633. doi:10.1038/cdd.2012.42

    CAS  PubMed  Google Scholar 

  49. Gloeckner CJ, Schumacher A, Boldt K, Ueffing M (2009) The Parkinson disease-associated protein kinase LRRK2 exhibits MAPKKK activity and phosphorylates MKK3/6 and MKK4/7, in vitro. J Neurochem 109(4):959–968. doi:10.1111/j.1471-4159.2009.06024.x

    CAS  PubMed  Google Scholar 

  50. Xu P, Das M, Reilly J, Davis RJ (2011) JNK regulates FoxO-dependent autophagy in neurons. Genes Dev 25(4):310–322. doi:10.1101/gad.1984311

    CAS  PubMed  Google Scholar 

  51. 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(5):1380–1388. doi:10.1021/bi061960m

    CAS  PubMed  Google Scholar 

  52. Daniels V, Vancraenenbroeck R, Law BM, Greggio E, Lobbestael E, Gao F, De Maeyer M, Cookson MR, Harvey K, Baekelandt V, Taymans JM (2011) Insight into the mode of action of the LRRK2 Y1699C pathogenic mutant. J Neurochem 116(2):304–315. doi:10.1111/j.1471-4159.2010.07105.x

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Lewis PA, Greggio E, Beilina A, Jain S, Baker A, Cookson MR (2007) The R1441C mutation of LRRK2 disrupts GTP hydrolysis. Biochem Biophys Res Commun 357(3):668–671

    CAS  PubMed Central  PubMed  Google Scholar 

  54. 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(24):16906–16914

    CAS  PubMed  Google Scholar 

  55. Xiong Y, Coombes CE, Kilaru A, Li X, Gitler AD, Bowers WJ, Dawson VL, Dawson TM, Moore DJ (2010) GTPase activity plays a key role in the pathobiology of LRRK2. PLoS Genet 6(4):e1000902. doi:10.1371/journal.pgen.1000902

    PubMed Central  PubMed  Google Scholar 

  56. Taymans JM (2012) The GTPase function of LRRK2. Biochem Soc Trans 40(5):1063–1069. doi:10.1042/BST20120133

    CAS  PubMed  Google Scholar 

  57. 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(5):1499–1504

    CAS  PubMed  Google Scholar 

  58. 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(8):e23207

    CAS  PubMed Central  PubMed  Google Scholar 

  59. Stafa K, Trancikova A, Webber PJ, Glauser L, West AB, Moore DJ (2012) GTPase activity and neuronal toxicity of Parkinson’s disease-associated LRRK2 is regulated by ArfGAP1. PLoS Genet 8(2):e1002526. doi:10.1371/journal.pgen.1002526

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Xiong Y, Yuan C, Chen R, Dawson TM, Dawson VL (2012) ArfGAP1 is a GTPase activating protein for LRRK2: reciprocal regulation of ArfGAP1 by LRRK2. J Neurosci 32(11):3877–3886. doi:10.1523/JNEUROSCI.4566-11.2012

    CAS  PubMed Central  PubMed  Google Scholar 

  61. 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(8):e43472

    CAS  PubMed Central  PubMed  Google Scholar 

  62. James NG, Digman MA, Gratton E, Barylko B, Ding X, Albanesi JP, Goldberg MS, Jameson DM (2012) Number and brightness analysis of LRRK2 oligomerization in live cells. Biophys J 102(11):L41–L43

    CAS  PubMed Central  PubMed  Google Scholar 

  63. 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(26):5511–5523

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Sen S, Webber PJ, West AB (2009) Dependence of leucine-rich repeat kinase 2 (LRRK2) kinase activity on dimerization. J Biol Chem 284(52):36346–36356

    CAS  PubMed  Google Scholar 

  65. 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(3):987–994. doi:10.1042/BJ20111215

    CAS  PubMed  Google Scholar 

  66. 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(3):703–715. doi:10.1111/j.1471-4159.2009.06358.x

    CAS  PubMed  Google Scholar 

  67. Alegre-Abarrategui J, Christian H, Lufino MM, Mutihac R, Venda LL, Ansorge O, Wade-Martins R (2009) LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model. Hum Mol Genet 18(21):4022–4034

    CAS  PubMed  Google Scholar 

  68. Guiet C, Vito P (2000) Caspase recruitment domain (CARD)-dependent cytoplasmic filaments mediate bcl10-induced NF-kappaB activation. J Cell Biol 148(6):1131–1140

    CAS  PubMed  Google Scholar 

  69. Siegel RM, Martin DA, Zheng L, Ng SY, Bertin J, Cohen J, Lenardo MJ (1998) Death-effector filaments: novel cytoplasmic structures that recruit caspases and trigger apoptosis. J Cell Biol 141(5):1243–1253

    CAS  PubMed  Google Scholar 

  70. Dzamko N, Deak M, Hentati F, Reith AD, Prescott AR, Alessi DR, Nichols RJ (2010) Inhibition of LRRK2 kinase activity leads to dephosphorylation of Ser(910)/Ser(935), disruption of 14–3-3 binding and altered cytoplasmic localization. Biochem J 430(3):405–413

    CAS  PubMed Central  PubMed  Google Scholar 

  71. 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(1):99–111

    CAS  PubMed  Google Scholar 

  72. 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(3):907–912. doi:10.1523/JNEUROSCI.5092-10.2011

    CAS  PubMed  Google Scholar 

  73. Lee BD, Shin JH, VanKampen J, Petrucelli L, West AB, Ko HS, Lee YI, Maguire-Zeiss KA, Bowers WJ, Federoff HJ, Dawson VL, Dawson TM (2010) Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson’s disease. Nat Med 16(9):998–1000

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Maekawa T, Mori S, Sasaki Y, Miyajima T, Azuma S, Ohta E, Obata F (2012) The I2020T Leucine-rich repeat kinase 2 transgenic mouse exhibits impaired locomotive ability accompanied by dopaminergic neuron abnormalities. Mol Neurodegener 7:15. doi:10.1186/1750-1326-7-15

    CAS  PubMed Central  PubMed  Google Scholar 

  75. 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(12):1303–1307. doi:10.1038/ng.485

    CAS  PubMed  Google Scholar 

  76. 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(12):1308–1312. doi:10.1038/ng.487

    CAS  PubMed Central  PubMed  Google Scholar 

  77. Guerreiro PS, Huang Y, Gysbers A, Cheng D, Gai WP, Outeiro TF, Halliday GM (2012) LRRK2 interactions with alpha-synuclein in Parkinson’s disease brains and in cell models. J Mol Med (Berl). doi:10.1007/s00109-012-0984-y

    Google Scholar 

  78. Qing H, Wong W, McGeer EG, McGeer PL (2009) Lrrk2 phosphorylates alpha synuclein at serine 129: Parkinson disease implications. Biochem Biophys Res Commun 387(1):149–152. doi:10.1016/j.bbrc.2009.06.142

    CAS  PubMed  Google Scholar 

  79. Lin X, Parisiadou L, Gu XL, Wang L, Shim H, Sun L, Xie C, Long CX, Yang WJ, Ding J, Chen ZZ, Gallant PE, Tao-Cheng JH, 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(6):807–827. doi:10.1016/j.neuron.2009.11.006

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Friedman LG, Lachenmayer ML, Wang J, He L, Poulose SM, Komatsu M, Holstein GR, Yue Z (2012) Disrupted autophagy leads to dopaminergic axon and dendrite degeneration and promotes presynaptic accumulation of alpha-synuclein and LRRK2 in the brain. J Neurosci 32(22):7585–7593. doi:10.1523/JNEUROSCI.5809-11.2012

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Carballo-Carbajal I, Weber-Endress S, Rovelli G, Chan D, Wolozin B, Klein CL, Patenge N, Gasser T, Kahle PJ (2010) Leucine-rich repeat kinase 2 induces alpha-synuclein expression via the extracellular signal-regulated kinase pathway. Cell Signal 22(5):821–827. doi:10.1016/j.cellsig.2010.01.006

    CAS  PubMed Central  PubMed  Google Scholar 

  82. 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(21):9879–9884. doi:10.1073/pnas.1004676107

    CAS  PubMed  Google Scholar 

  83. Daher JP, Pletnikova O, Biskup S, Musso A, Gellhaar S, Galter D, Troncoso JC, Lee MK, Dawson TM, Dawson VL, Moore DJ (2012) Neurodegenerative phenotypes in an A53T alpha-synuclein transgenic mouse model are independent of LRRK2. Hum Mol Genet 21(11):2420–2431. doi:10.1093/hmg/dds057

    CAS  PubMed  Google Scholar 

  84. Herzig MC, Bidinosti M, Schweizer T, Hafner T, Stemmelen C, Weiss A, Danner S, Vidotto N, Stauffer D, Barske C, Mayer F, Schmid P, Rovelli G, van der Putten PH, Shimshek DR (2012) High LRRK2 levels fail to induce or exacerbate neuronal alpha-synucleinopathy in mouse brain. PLoS ONE 7(5):e36581. doi:10.1371/journal.pone.0036581

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Kondo K, Obitsu S, Teshima R (2011) alpha-Synuclein aggregation and transmission are enhanced by leucine-rich repeat kinase 2 in human neuroblastoma SH-SY5Y cells. Biol Pharm Bull 34(7):1078–1083

    CAS  PubMed  Google Scholar 

  86. Danzer KM, Kranich LR, Ruf WP, Cagsal-Getkin O, Winslow AR, Zhu L, Vanderburg CR, McLean PJ (2012) Exosomal cell-to-cell transmission of alpha synuclein oligomers. Mol Neurodegener 7:42. doi:10.1186/1750-1326-7-42

    CAS  PubMed Central  PubMed  Google Scholar 

  87. Vekrellis K, Stefanis L (2012) Targeting intracellular and extracellular alpha-synuclein as a therapeutic strategy in Parkinson’s disease and other synucleinopathies. Expert Opin Ther Targets 16(4):421–432. doi:10.1517/14728222.2012.674111

    CAS  PubMed  Google Scholar 

  88. Ostrerova N, Petrucelli L, Farrer M, Mehta N, Choi P, Hardy J, Wolozin B (1999) Alpha-Synuclein shares physical and functional homology with 14–3-3 proteins. J Neurosci 19(14):5782–5791

    CAS  PubMed  Google Scholar 

  89. McFarland MA, Ellis CE, Markey SP, Nussbaum RL (2008) Proteomics analysis identifies phosphorylation-dependent alpha-synuclein protein interactions. Mol Cell Proteomics 7(11):2123–2137. doi:10.1074/mcp.M800116-MCP200

    CAS  PubMed  Google Scholar 

  90. 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(3):393–404

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Taymans JM, Cookson MR (2010) Mechanisms in dominant parkinsonism: the toxic triangle of LRRK2, alpha-synuclein, and tau. BioEssays 32(3):227–235

    CAS  PubMed  Google Scholar 

  92. Vekrellis K, Xilouri M, Emmanouilidou E, Rideout HJ, Stefanis L (2011) Pathological roles of alpha-synuclein in neurological disorders. Lancet Neurol 10(11):1015–1025. doi:10.1016/S1474-4422(11)70213-7

    CAS  PubMed  Google Scholar 

  93. Muntane G, Dalfo E, Martinez A, Ferrer I (2008) Phosphorylation of tau and alpha-synuclein in synaptic-enriched fractions of the frontal cortex in Alzheimer’s disease, and in Parkinson’s disease and related alpha-synucleinopathies. Neuroscience 152(4):913–923. doi:10.1016/j.neuroscience.2008.01.030

    CAS  PubMed  Google Scholar 

  94. Haggerty T, Credle J, Rodriguez O, Wills J, Oaks AW, Masliah E, Sidhu A (2011) Hyperphosphorylated Tau in an alpha-synuclein-overexpressing transgenic model of Parkinson’s disease. Eur J Neurosci 33(9):1598–1610. doi:10.1111/j.1460-9568.2011.07660.x

    PubMed Central  PubMed  Google Scholar 

  95. Melrose HL, Dachsel JC, Behrouz B, Lincoln SJ, Yue M, Hinkle KM, Kent CB, Korvatska E, Taylor JP, Witten L, Liang YQ, 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(3):503–517. doi:10.1016/j.nbd.2010.07.010

    CAS  PubMed Central  PubMed  Google Scholar 

  96. Dachsel JC, Mata IF, Ross OA, Taylor JP, Lincoln SJ, Hinkle KM, Huerta C, Ribacoba R, Blazquez M, Alvarez V, Farrer MJ (2006) Digenic Parkinsonism: investigation of the synergistic effects of PRKN and LRRK2. Neurosci Lett 410(2):80–84. doi:10.1016/j.neulet.2006.06.068

    PubMed  Google Scholar 

  97. Ng CH, Mok SZ, Koh C, Ouyang X, Fivaz ML, Tan EK, Dawson VL, Dawson TM, Yu F, Lim KL (2009) Parkin protects against LRRK2 G2019S mutant-induced dopaminergic neurodegeneration in Drosophila. J Neurosci 29(36):11257–11262. doi:10.1523/JNEUROSCI.2375-09.2009

    CAS  PubMed Central  PubMed  Google Scholar 

  98. Venderova K, Kabbach G, Abdel-Messih E, Zhang Y, Parks RJ, Imai Y, Gehrke S, Ngsee J, Lavoie MJ, Slack RS, Rao Y, Zhang Z, Lu B, Haque ME, Park DS (2009) 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 18(22):4390–4404. doi:10.1093/hmg/ddp394

    CAS  PubMed  Google Scholar 

  99. Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D (2004) Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305(5688):1292–1295. doi:10.1126/science.1101738

    CAS  PubMed  Google Scholar 

  100. Vogiatzi T, Xilouri M, Vekrellis K, Stefanis L (2008) Wild type alpha-synuclein is degraded by chaperone-mediated autophagy and macroautophagy in neuronal cells. J Biol Chem 283(35):23542–23556. doi:10.1074/jbc.M801992200

    CAS  PubMed  Google Scholar 

  101. Xilouri M, Vogiatzi T, Vekrellis K, Park D, Stefanis L (2009) Abberant alpha-synuclein confers toxicity to neurons in part through inhibition of chaperone-mediated autophagy. PLoS ONE 4(5):e5515. doi:10.1371/journal.pone.0005515

    PubMed Central  PubMed  Google Scholar 

  102. Lachenmayer ML, Yue Z (2012) Genetic animal models for evaluating the role of autophagy in etiopathogenesis of Parkinson disease. Autophagy 8(12):1837–1838. doi:10.4161/auto.21859

    CAS  PubMed  Google Scholar 

  103. Gomez-Suaga P, Luzon-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(3):511–525. doi:10.1093/hmg/ddr481

    CAS  PubMed  Google Scholar 

  104. Anand VS, Reichling LJ, Lipinski K, Stochaj W, Duan W, Kelleher K, Pungaliya P, Brown EL, Reinhart PH, Somberg R, Hirst WD, Riddle SM, Braithwaite SP (2009) Investigation of leucine-rich repeat kinase 2: enzymological properties and novel assays. FEBS J 276(2):466–478. doi:10.1111/j.1742-4658.2008.06789.x

    CAS  PubMed  Google Scholar 

  105. Biskup S, Moore DJ, Celsi F, Higashi S, West AB, Andrabi SA, Kurkinen K, Yu SW, Savitt JM, Waldvogel HJ, Faull RL, 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(5):557–569

    CAS  PubMed  Google Scholar 

  106. 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(6):2225–2237. doi:10.1523/JNEUROSCI.3730-10.2011

    CAS  PubMed  Google Scholar 

  107. Shin N, Jeong H, Kwon J, Heo HY, Kwon JJ, Yun HJ, Kim CH, Han BS, Tong Y, Shen J, Hatano T, Hattori N, Kim KS, Chang S, Seol W (2008) LRRK2 regulates synaptic vesicle endocytosis. Exp Cell Res 314(10):2055–2065. doi:10.1016/j.yexcr.2008.02.015

    CAS  PubMed  Google Scholar 

  108. Fischer von Mollard G, Stahl B, Walch-Solimena C, Takei K, Daniels L, Khoklatchev A, De Camilli P, Sudhof TC, Jahn R (1994) Localization of Rab5 to synaptic vesicles identifies endosomal intermediate in synaptic vesicle recycling pathway. Eur J Cell Biol 65(2):319–326

    CAS  PubMed  Google Scholar 

  109. Gallop JL, Jao CC, Kent HM, Butler PJ, Evans PR, Langen R, McMahon HT (2006) Mechanism of endophilin N-BAR domain-mediated membrane curvature. EMBO J 25(12):2898–2910. doi:10.1038/sj.emboj.7601174

    CAS  PubMed  Google Scholar 

  110. Matta S, Van Kolen K, da Cunha R, van den Bogaart G, Mandemakers W, Miskiewicz K, De Bock PJ, Morais VA, Vilain S, Haddad D, Delbroek L, Swerts J, Chavez-Gutierrez 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(6):1008–1021. doi:10.1016/j.neuron.2012.08.022

    CAS  PubMed  Google Scholar 

  111. Andres-Mateos E, Mejias R, Sasaki M, Li X, Lin BM, Biskup S, Zhang L, Banerjee R, Thomas B, Yang L, Liu G, Beal MF, Huso DL, Dawson TM, Dawson VL (2009) Unexpected lack of hypersensitivity in LRRK2 knock-out mice to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). J Neurosci 29(50):15846–15850. doi:10.1523/JNEUROSCI.4357-09.2009

    CAS  PubMed Central  PubMed  Google Scholar 

  112. Li X, Patel JC, Wang J, Avshalumov MV, Nicholson C, Buxbaum JD, Elder GA, Rice ME, Yue Z (2010) Enhanced striatal dopamine transmission and motor performance with LRRK2 overexpression in mice is eliminated by familial Parkinson’s disease mutation G2019S. J Neurosci 30(5):1788–1797. doi:10.1523/JNEUROSCI.5604-09.2010

    CAS  PubMed Central  PubMed  Google Scholar 

  113. 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(34):14622–14627. doi:10.1073/pnas.0906334106

    CAS  PubMed  Google Scholar 

  114. Greggio E, Lewis PA, van der Brug MP, Ahmad R, Kaganovich A, Ding J, Beilina A, Baker AK, Cookson MR (2007) Mutations in LRRK2/dardarin associated with Parkinson disease are more toxic than equivalent mutations in the homologous kinase LRRK1. J Neurochem 102(1):93–102

    CAS  PubMed  Google Scholar 

  115. Umeno J, Asano K, Matsushita T, Matsumoto T, Kiyohara Y, Iida M, Nakamura Y, Kamatani N, Kubo M (2011) Meta-analysis of published studies identified eight additional common susceptibility loci for Crohn’s disease and ulcerative colitis. Inflamm Bowel Dis 17(12):2407–2415. doi:10.1002/ibd.21651

    PubMed  Google Scholar 

  116. Park JH, Kim YG, McDonald C, Kanneganti TD, Hasegawa M, Body-Malapel M, Inohara N, Nunez G (2007) RICK/RIP2 mediates innate immune responses induced through Nod1 and Nod2 but not TLRs. J Immunol 178(4):2380–2386

    CAS  PubMed  Google Scholar 

  117. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, Almer S, Tysk C, O’Morain CA, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-Puig P, Gower-Rousseau C, Macry J, Colombel JF, Sahbatou M, Thomas G (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411(6837):599–603. doi:10.1038/35079107

    CAS  PubMed  Google Scholar 

  118. 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(11):1063–1070. doi:10.1038/ni.2113

    CAS  PubMed  Google Scholar 

  119. Weigmann B, Lehr HA, Yancopoulos G, Valenzuela D, Murphy A, Stevens S, Schmidt J, Galle PR, Rose-John S, Neurath MF (2008) The transcription factor NFATc2 controls IL-6-dependent T cell activation in experimental colitis. J Exp Med 205(9):2099–2110. doi:10.1084/jem.20072484

    CAS  PubMed Central  PubMed  Google Scholar 

  120. Elloumi HZ, Maharshak N, Rao KN, Kobayashi T, Ryu HS, Muhlbauer M, Li F, Jobin C, Plevy SE (2012) A cell permeable peptide inhibitor of NFAT inhibits macrophage cytokine expression and ameliorates experimental colitis. PLoS ONE 7(3):e34172. doi:10.1371/journal.pone.0034172

    CAS  PubMed Central  PubMed  Google Scholar 

  121. Milosevic J, Schwarz SC, Ogunlade V, Meyer AK, Storch A, Schwarz J (2009) Emerging role of LRRK2 in human neural progenitor cell cycle progression, survival and differentiation. Mol Neurodegener 4:25. doi:10.1186/1750-1326-4-25

    PubMed Central  PubMed  Google Scholar 

  122. Schulz C, Paus M, Frey K, Schmid R, Kohl Z, Mennerich D, Winkler J, Gillardon F (2011) Leucine-rich repeat kinase 2 modulates retinoic acid-induced neuronal differentiation of murine embryonic stem cells. PLoS ONE 6(6):e20820. doi:10.1371/journal.pone.0020820

    CAS  PubMed Central  PubMed  Google Scholar 

  123. Gillardon F, Schmid R, Draheim H (2012) Parkinson’s disease-linked leucine-rich repeat kinase 2(R1441G) mutation increases proinflammatory cytokine release from activated primary microglial cells and resultant neurotoxicity. Neuroscience 208:41–48

    CAS  PubMed  Google Scholar 

  124. 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(5):1602–1611

    CAS  PubMed Central  PubMed  Google Scholar 

  125. 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(5):795–808. doi:10.1007/s00702-011-0653-2

    CAS  PubMed Central  PubMed  Google Scholar 

  126. 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(9):5577–5585. doi:10.4049/jimmunol.1000548

    CAS  PubMed Central  PubMed  Google Scholar 

  127. 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(6):e39132

    CAS  PubMed Central  PubMed  Google Scholar 

  128. Exner N, Lutz AK, Haass C, Winklhofer KF (2012) Mitochondrial dysfunction in Parkinson’s disease: molecular mechanisms and pathophysiological consequences. EMBO J 31(14):3038–3062. doi:10.1038/emboj.2012.170

    CAS  PubMed  Google Scholar 

  129. Schapira AH (2010) Complex I: inhibitors, inhibition and neurodegeneration. Exp Neurol 224(2):331–335. doi:10.1016/j.expneurol.2010.03.028

    CAS  PubMed  Google Scholar 

  130. Cui J, Yu M, Niu J, Yue Z, Xu Z (2012) Expression of Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibits the Processing of uMtCK to Induce Cell Death in cell culture model system. Biosci Rep

  131. Mortiboys H, Johansen KK, Aasly JO, Bandmann O (2012) Mitochondrial impairment in patients with Parkinson disease with the G2019S mutation in LRRK2. Neurology 75(22):2017–2020

    Google Scholar 

  132. Papkovskaia TD, Chau KY, Inesta-Vaquera F, Papkovsky DB, Healy DG, Nishio K, Staddon J, Duchen MR, Hardy J, Schapira AH, Cooper JM (2012) G2019S leucine-rich repeat kinase 2 causes uncoupling protein-mediated mitochondrial depolarization. Hum Mol Genet 21(19):4201–4213. doi:10.1093/hmg/dds244

    CAS  PubMed  Google Scholar 

  133. Wang X, Yan MH, Fujioka H, Liu J, Wilson-Delfosse A, Chen SG, Perry G, Casadesus G, Zhu X (2012) LRRK2 regulates mitochondrial dynamics and function through direct interaction with DLP1. Hum Mol Genet 21(9):1931–1944. doi:10.1093/hmg/dds003

    CAS  PubMed  Google Scholar 

  134. Cooper O, Seo H, Andrabi S, Guardia-Laguarta C, Graziotto J, Sundberg M, McLean JR, Carrillo-Reid L, Xie Z, Osborn T, Hargus G, Deleidi M, Lawson T, Bogetofte H, Perez-Torres E, Clark L, Moskowitz C, Mazzulli J, Chen L, Volpicelli-Daley L, Romero N, Jiang H, Uitti RJ, Huang Z, Opala G, Scarffe LA, Dawson VL, Klein C, Feng J, Ross OA, Trojanowski JQ, Lee VM, Marder K, Surmeier DJ, Wszolek ZK, Przedborski S, Krainc D, Dawson TM, Isacson O (2012) Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson’s disease. Sci Transl Med 4(141):141ra190. doi:10.1126/scitranslmed.3003985

    Google Scholar 

  135. Samann J, Hegermann J, von Gromoff E, Eimer S, Baumeister R, Schmidt E (2009) Caenorhabditits elegans LRK-1 and PINK-1 act antagonistically in stress response and neurite outgrowth. J Biol Chem 284(24):16482–16491. doi:10.1074/jbc.M808255200

    PubMed  Google Scholar 

  136. Zhou H, Huang C, Tong J, Hong WC, Liu YJ, Xia XG (2011) Temporal expression of mutant LRRK2 in adult rats impairs dopamine reuptake. Int J Biol Sci 7(6):753–761

    CAS  PubMed Central  PubMed  Google Scholar 

  137. 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(21):4209–4223. doi:10.1093/hmg/ddr348

    CAS  PubMed  Google Scholar 

  138. Berwick DC, Harvey K (2012) LRRK2 functions as a Wnt signaling scaffold, bridging cytosolic proteins and membrane-localized LRP6. Hum Mol Genet 21(22):4966–4979. doi:10.1093/hmg/dds342

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by an International Research Grants Program award from the Parkinson’s Disease Foundation (HJR), HJR is currently supported by an Innovation Grant from Parkinson’s UK (K-1208); and by the Hellenic General Secretariat of Research and Technology (“SINERGASIA”, 09ΣΥΝ-12-876; LS).

Author information

Authors and Affiliations

  1. Laboratory of Neurodegenerative Diseases, Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens, Soranou Efesiou 4, 11527, Athens, Greece

    Hardy J. Rideout & Leonidas Stefanis

  2. Second Department of Neurology, University of Athens Medical School, Athens, Greece

    Leonidas Stefanis

Authors
  1. Hardy J. Rideout
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Leonidas Stefanis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hardy J. Rideout.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rideout, H.J., Stefanis , L. The Neurobiology of LRRK2 and its Role in the Pathogenesis of Parkinson’s Disease. Neurochem Res 39, 576–592 (2014). https://doi.org/10.1007/s11064-013-1073-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-013-1073-5

Keywords

Search

Navigation