Skip to main content
Springer Nature Link
Log in

Understanding the GTPase Activity of LRRK2: Regulation, Function, and Neurotoxicity

  • Chapter
  • First Online:
Leucine-Rich Repeat Kinase 2 (LRRK2)

Part of the book series: Advances in Neurobiology ((NEUROBIOL,volume 14))

Abstract

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of Parkinson’s disease (PD) with late-onset and autosomal-dominant inheritance. LRRK2 belongs to the ROCO superfamily of proteins, characterized by a Ras-of-complex (Roc) GTPase domain in tandem with a C-terminal-of-Roc (COR) domain. LRRK2 also contains a protein kinase domain adjacent to the Roc-COR tandem domain in addition to multiple repeat domains. Disease-causing familial mutations cluster within the Roc-COR tandem and kinase domains of LRRK2, where they act to either impair GTPase activity or enhance kinase activity. Familial LRRK2 mutations share in common the capacity to induce neuronal toxicity in cultured cells. While the contribution of the frequent G2019S mutation, located within the kinase domain, to kinase activity and neurotoxicity has been extensively investigated, the contribution of GTPase activity has received less attention. The GTPase domain has been shown to play an important role in regulating kinase activity, in dimerization, and in mediating the neurotoxic effects of LRRK2. Accordingly, the GTPase domain has emerged as a potential therapeutic target for inhibiting the pathogenic effects of LRRK2 mutations. Many important mechanisms remain to be elucidated, including how the GTPase cycle of LRRK2 is regulated, whether GTPase effectors exist for LRRK2, and how GTPase activity contributes to the overall functional output of LRRK2. In this review, we discuss the importance of the GTPase domain for LRRK2-linked PD focusing in particular on its regulation, function, and contribution to neurotoxic mechanisms.

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

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (Canada)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (Canada)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (Canada)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (Canada)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Gasser T (2009) Mendelian forms of Parkinson’s disease. Biochim Biophys Acta 1792:587–596

    Article  CAS  PubMed  Google Scholar 

  2. 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 AHV, Lynch T, Bhatia KP, Gasser T, Lees AJ, Wood NW (2008) Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case–control study. Lancet Neurol 7(7):583–590. doi:10.1016/S1474-4422(08)70117-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Paisán-Ruiz C, Jain S, Evans EW, Gilks WP, Simón J, van der Brug M, de Munain AL, Aparicio S, Gil AM, Khan N, Johnson J, Martinez JR, Nicholl D, Carrera IM, Pena AS, de Silva R, Lees A, MartI-Massó JF, Pérez-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

    Article  PubMed  Google Scholar 

  4. 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, Müller-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

    Article  CAS  PubMed  Google Scholar 

  5. 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

    Article  CAS  PubMed  Google Scholar 

  6. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Nalls MA, Pankratz N, Lill CM, Do CB, Hernandez DG, Saad M, DeStefano AL, Kara E, Bras J, Sharma M, Schulte C, Keller MF, Arepalli S, Letson C, Edsall C, Stefansson H, Liu X, Pliner H, Lee JH, Cheng R, International Parkinson’s Disease Genomics Consortium (IPDGC), Parkinson’s Study Group (PSG) Parkinson’s Research: The Organized GENetics Initiative (PROGENI), 23andMe, GenePD, NeuroGenetics Research Consortium (NGRC), Hussman Institute of Human Genomics (HIHG), Ashkenazi Jewish Dataset Investigator, Cohorts for Health and Aging Research in Genetic Epidemiology (CHARGE), North American Brain Expression Consortium (NABEC), United Kingdom Brain Expression Consortium (UKBEC), Greek Parkinson’s Disease Consortium, Alzheimer Genetic Analysis Group, Ikram MA, Ioannidis JP, Hadjigeorgiou GM, Bis JC, Martinez M, Perlmutter JS, Goate A, Marder K, Fiske B, Sutherland M, Xiromerisiou G, Myers RH, Clark LN, Stefansson K, Hardy JA, Heutink P, Chen H, Wood NW, Houlden H, Payami H, Brice A, Scott WK, Gasser T, Bertram L, Eriksson N, Foroud T, Singleton AB (2014) Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat Genet 46(9):989–993. doi:10.1038/ng.3043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Biskup S, West AB (2009) Zeroing in on LRRK2-linked pathogenic mechanisms in Parkinson’s disease. Biochim Biophys Acta 1792(7):625–633. doi:10.1016/j.bbadis.2008.09.015

    Article  CAS  PubMed  Google Scholar 

  9. Aasly JO, Vilariño-Güell 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(13):2156–2163. doi:10.1002/mds.23265

    Article  PubMed  PubMed Central  Google Scholar 

  10. Hulihan MM, Ishihara-Paul L, Kachergus J, Warren L, Amouri R, Elango R, Prinjha RK, Upmanyu R, Kefi M, Zouari M, Sassi SB, Yahmed SB, El Euch-Fayeche G, Matthews PM, Middleton LT, Gibson RA, Hentati F, Farrer MJ (2008) LRRK2 Gly2019Ser penetrance in Arab-Berber patients from Tunisia: a case–control genetic study. Lancet Neurol 7(7):591–594. doi:10.1016/S1474-4422(08)70116-9

    Article  CAS  PubMed  Google Scholar 

  11. Tsika E, Moore DJ (2013) Contribution of GTPase activity to LRRK2-associated Parkinson disease. Small GTPases 4(3):164–170. doi:10.4161/sgtp.25130

    Article  PubMed  PubMed Central  Google Scholar 

  12. 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. doi:10.1021/bi100157u

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Greggio E, Zambrano I, Kaganovich A, Beilina A, Taymans J-M, Daniëls 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. doi:10.1074/jbc.M708718200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 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. doi:10.1074/jbc.M109.025437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Biosa A, Trancikova A, Civiero L, Glauser L, Bubacco L, Greggio E, Moore DJ (2013) GTPase activity regulates kinase activity and cellular phenotypes of Parkinson’s disease-associated LRRK2. Hum Mol Genet 22(6):1140–1156. doi:10.1093/hmg/dds522

    Article  CAS  PubMed  Google Scholar 

  16. 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 U S A 105(5):1499–1504. doi:10.1073/pnas.0709098105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gilsbach BK, Ho FY, Vetter IR, van Haastert PJ, Wittinghofer A, Kortholt A (2012) Roco kinase structures give insights into the mechanism of Parkinson disease-related leucine-rich-repeat kinase 2 mutations. Proc Natl Acad Sci U S A 109(26):10322–10327. doi:10.1073/pnas.1203223109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  21. Bosgraaf L, Van Haastert PJM (2003) Roc, a Ras/GTPase domain in complex proteins. Biochim Biophys Acta 1643(1–3):5–10. doi:10.1016/j.bbamcr.2003.08.008

    Article  CAS  PubMed  Google Scholar 

  22. 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(6):423–429

    Article  CAS  PubMed  Google Scholar 

  23. Gotthardt K, Weyand M, Kortholt A, Van Haastert PJM, 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(16):2239–2249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Civiero L, Dihanich S, Lewis PA, Greggio E (2014) Genetic, structural, and molecular insights into the function of ras of complex proteins domains. Chem Biol 21(7):809–818. doi:10.1016/j.chembiol.2014.05.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gilsbach BK, Kortholt A (2014) Structural biology of the LRRK2 GTPase and kinase domains: implications for regulation. Front Mol Neurosci 7:32. doi:10.3389/fnmol.2014.00032

    Article  PubMed  PubMed Central  Google Scholar 

  26. 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

    Article  PubMed  Google Scholar 

  27. Tan EK, Peng R, Teo YY, Tan LC, Angeles D, Ho P, Chen ML, Lin CH, Mao XY, Chang XL, Prakash KM, Liu JJ, Au WL, Le WD, Jankovic J, Burgunder JM, Zhao Y, Wu RM (2010) Multiple LRRK2 variants modulate risk of Parkinson disease: a Chinese multicenter study. Hum Mutat 31(5):561–568. doi:10.1002/humu.21225

    CAS  PubMed  Google Scholar 

  28. Ross OA, Soto-Ortolaza AI, Heckman MG, Aasly JO, Abahuni N, Annesi G, Bacon JA, Bardien S, Bozi M, Brice A, Brighina L, Van Broeckhoven C, Carr J, Chartier-Harlin MC, Dardiotis E, Dickson DW, Diehl NN, Elbaz A, Ferrarese C, Ferraris A, Fiske B, Gibson JM, Gibson R, Hadjigeorgiou GM, Hattori N, Ioannidis JP, Jasinska-Myga B, Jeon BS, Kim YJ, Klein C, Kruger R, Kyratzi E, Lesage S, Lin CH, Lynch T, Maraganore DM, Mellick GD, Mutez E, Nilsson C, Opala G, Park SS, Puschmann A, Quattrone A, Sharma M, Silburn PA, Sohn YH, Stefanis L, Tadic V, Theuns J, Tomiyama H, Uitti RJ, Valente EM, van de Loo S, Vassilatis DK, Vilarino-Guell C, White LR, Wirdefeldt K, Wszolek ZK, Wu RM, Farrer MJ, Genetic Epidemiology of Parkinson’s Disease (GEO-PD) Consortium. (2011) Association of LRRK2 exonic variants with susceptibility to Parkinson’s disease: a case–control study. Lancet Neurol 10(10):898–908. doi:10.1016/S1474-4422(11)70175-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Heckman MG, Soto-Ortolaza AI, Aasly JO, Abahuni N, Annesi G, Bacon JA, Bardien S, Bozi M, Brice A, Brighina L, Carr J, Chartier-Harlin MC, Dardiotis E, Dickson DW, Diehl NN, Elbaz A, Ferrarese C, Fiske B, Gibson JM, Gibson R, Hadjigeorgiou GM, Hattori N, Ioannidis JP, Boczarska-Jedynak M, Jasinska-Myga B, Jeon BS, Kim YJ, Klein C, Kruger R, Kyratzi E, Lesage S, Lin CH, Lynch T, Maraganore DM, Mellick GD, Mutez E, Nilsson C, Opala G, Park SS, Petrucci S, Puschmann A, Quattrone A, Sharma M, Silburn PA, Sohn YH, Stefanis L, Tadic V, Theuns J, Tomiyama H, Uitti RJ, Valente EM, Van Broeckhoven C, van de Loo S, Vassilatis DK, Vilarino-Guell C, White LR, Wirdefeldt K, Wszolek ZK, Wu RM, Hentati F, Farrer MJ, Ross OA, Genetic Epidemiology of Parkinson’s Disease (GEO-PD) Consortium (2013) Population-specific frequencies for LRRK2 susceptibility variants in the Genetic Epidemiology of Parkinson’s Disease (GEO-PD) Consortium. Mov Disord 28(12):1740–1744. doi:10.1002/mds.25600

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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 J Neurol 128(Pt 12):2786–2796. doi:10.1093/brain/awh667

    Article  Google Scholar 

  31. 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

    Article  CAS  PubMed  Google Scholar 

  32. 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. doi:10.1016/j.bbrc.2007.04.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Li X, Tan Y-C, Poulose S, Olanow CW, Huang X-Y, 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  PubMed Central  Google Scholar 

  34. 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

    Article  CAS  PubMed  Google Scholar 

  35. West AB, Moore DJ, Choi C, Andrabi SA, Li X, Dikeman D, Biskup S, Zhang Z, Lim K-L, Dawson VL, Dawson TM (2007) Parkinson’s disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Hum Mol Genet 16(2):223–232. doi:10.1093/hmg/ddl471

    Article  CAS  PubMed  Google Scholar 

  36. Daniëls V, Vancraenenbroeck R, Law BMH, Greggio E, Lobbestael E, Gao F, De Maeyer M, Cookson MR, Harvey K, Baekelandt V, Taymans J-M (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

    Article  PubMed  PubMed Central  Google Scholar 

  37. 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

    Article  PubMed  PubMed Central  Google Scholar 

  38. Liao J, Wu CX, Burlak C, Zhang S, Sahm H, Wang M, Zhang ZY, Vogel KW, Federici M, Riddle SM, Nichols RJ, Liu D, Cookson MR, Stone TA, Hoang QQ (2014) Parkinson disease-associated mutation R1441H in LRRK2 prolongs the “active state” of its GTPase domain. Proc Natl Acad Sci U S A 111(11):4055–4060. doi:10.1073/pnas.1323285111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 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 U S A 102(46):16842–16847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Taymans J-M, 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. doi:10.1371/journal.pone.0023207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Haebig K, Gloeckner CJ, Miralles MG, Gillardon F, Schulte C, Riess O, Ueffing M, Biskup S, Bonin M (2010) ARHGEF7 (beta-PIX) acts as guanine nucleotide exchange factor for leucine-rich repeat kinase 2. PLoS One 5(10), e13762. doi:10.1371/journal.pone.0013762

    Article  PubMed  PubMed Central  Google Scholar 

  44. Chia R, Haddock S, Beilina A, Rudenko IN, Mamais A, Kaganovich A, Li Y, Kumaran R, Nalls MA, Cookson MR (2014) Phosphorylation of LRRK2 by casein kinase 1alpha regulates trans-Golgi clustering via differential interaction with ARHGEF7. Nat Commun 5:5827. doi:10.1038/ncomms6827

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Dusonchet J, Li H, Guillily M, Liu M, Stafa K, Derada Troletti C, Boon JY, Saha S, Glauser L, Mamais A, Citro A, Youmans KL, Liu L, Schneider BL, Aebischer P, Yue Z, Bandopadhyay R, Glicksman MA, Moore DJ, Collins JJ, Wolozin B (2014) A Parkinson’s disease gene regulatory network identifies the signaling protein RGS2 as a modulator of LRRK2 activity and neuronal toxicity. Hum Mol Genet 23(18):4887–4905. doi:10.1093/hmg/ddu202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Terheyden S, Ho FY, Gilsbach BK, Wittinghofer A, Kortholt A (2015) Revisiting the Roco G-protein cycle. Biochem J 465(1):139–147. doi:10.1042/BJ20141095

    Article  CAS  PubMed  Google Scholar 

  48. Jorgensen ND, Peng Y, Ho CC, Rideout HJ, Petrey D, Liu P, Dauer WT (2009) The WD40 domain is required for LRRK2 neurotoxicity. PLoS One 4(12), e8463. doi:10.1371/journal.pone.0008463

    Article  PubMed  PubMed Central  Google Scholar 

  49. Liu Z, Mobley JA, DeLucas LJ, Kahn RA, West AB (2016) LRRK2 autophosphorylation enhances its GTPase activity. FASEB J 30(1):336–347. doi:10.1096/fj.15-277095

  50. 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

    Article  CAS  PubMed  Google Scholar 

  51. 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. doi:10.1016/j.bbrc.2009.08.163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kamikawaji S, Ito G, Iwatsubo T (2009) Identification of the autophosphorylation sites of LRRK2. Biochemistry 48(46):10963–10975. doi:10.1021/bi9011379

    Article  CAS  PubMed  Google Scholar 

  53. 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. doi:10.1016/j.jmb.2011.07.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 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 Trans Med 4(164), 164ra161. doi:10.1126/scitranslmed.3004485

    Article  Google Scholar 

  55. Muda K, Bertinetti D, Gesellchen F, Hermann JS, von Zweydorf F, Geerlof A, Jacob A, Ueffing M, Gloeckner CJ, Herberg FW (2014) Parkinson-related LRRK2 mutation R1441C/G/H impairs PKA phosphorylation of LRRK2 and disrupts its interaction with 14-3-3. Proc Natl Acad Sci U S A 111(1):E34–E43. doi:10.1073/pnas.1312701111

    Article  CAS  PubMed  Google Scholar 

  56. 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

    Article  CAS  PubMed  Google Scholar 

  57. 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 leucine-rich repeat kinase-2 protect against models of Parkinson’s disease. Nat Med 16(9):998–1000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. MacLeod D, Dowman J, Hammond R, Leete T, Inoue K, Abeliovich A (2006) The familial Parkinsonism gene LRRK2 regulates neurite process morphology. Neuron 52(4):587–593

    Article  CAS  PubMed  Google Scholar 

  59. Ramsden N, Perrin J, Ren Z, Lee BD, Zinn N, Dawson VL, Tam D, Bova M, Lang M, Drewes G, Bantscheff M, Bard F, Dawson TM, Hopf C (2011) Chemoproteomics-based design of potent LRRK2-selective lead compounds that attenuate Parkinson’s disease-related toxicity in human neurons. ACS Chem Biol 6(10):1021–1028. doi:10.1021/cb2002413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Manzoni C, Mamais A, Dihanich S, Abeti R, Soutar MP, Plun-Favreau H, Giunti P, Tooze SA, Bandopadhyay R, Lewis PA (2013) Inhibition of LRRK2 kinase activity stimulates macroautophagy. Biochim Biophys Acta 1833(12):2900–2910. doi:10.1016/j.bbamcr.2013.07.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Manzoni C, Mamais A, Dihanich S, McGoldrick P, Devine MJ, Zerle J, Kara E, Taanman JW, Healy DG, Marti-Masso JF, Schapira AH, Plun-Favreau H, Tooze S, Hardy J, Bandopadhyay R, Lewis PA (2013) Pathogenic Parkinson’s disease mutations across the functional domains of LRRK2 alter the autophagic/lysosomal response to starvation. Biochem Biophys Res Commun 441(4):862–866. doi:10.1016/j.bbrc.2013.10.159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. 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. doi:10.1093/hmg/ddp346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Daniel G, Moore DJ (2015) Modeling LRRK2 pathobiology in Parkinson’s disease: from yeast to rodents. Curr Top Behav Neurosci 22:331–368. doi:10.1007/7854_2014_311

    Article  CAS  PubMed  Google Scholar 

  66. Godena VK, Brookes-Hocking N, Moller A, Shaw G, Oswald M, Sancho RM, Miller CC, Whitworth AJ, De Vos KJ (2014) Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations. Nat Commun 5:5245. doi:10.1038/ncomms6245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Tagliaferro P, Kareva T, Oo TF, Yarygina O, Kholodilov N, Burke RE (2015) An early axonopathy in a hLRRK2(R1441G) transgenic model of Parkinson disease. Neurobiol Dis 82:359–371. doi:10.1016/j.nbd.2015.07.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. 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 U S A 106(34):14622–14627. doi:10.1073/pnas.0906334106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Tsika E, Kannan M, Foo CS, Dikeman D, Glauser L, Gellhaar S, Galter D, Knott GW, Dawson TM, Dawson VL, Moore DJ (2014) Conditional expression of Parkinson’s disease-related R1441C LRRK2 in midbrain dopaminergic neurons of mice causes nuclear abnormalities without neurodegeneration. Neurobiol Dis 71:345–358. doi:10.1016/j.nbd.2014.08.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Tsika E, Nguyen AP, Dusonchet J, Colin P, Schneider BL, Moore DJ (2015) Adenoviral-mediated expression of G2019S LRRK2 induces striatal pathology in a kinase-dependent manner in a rat model of Parkinson’s disease. Neurobiol Dis 77:49–61. doi:10.1016/j.nbd.2015.02.019

    Article  CAS  PubMed  Google Scholar 

  72. Daher JP, Abdelmotilib HA, Hu X, Volpicelli-Daley LA, Moehle MS, Fraser KB, Needle E, Chen Y, Steyn SJ, Galatsis P, Hirst WD, West AB (2015) Leucine-rich repeat kinase 2 (LRRK2) pharmacological inhibition abates alpha-synuclein gene-induced neurodegeneration. J Biol Chem 290(32):19433–19444. doi:10.1074/jbc.M115.660001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Li T, Yang D, Zhong S, Thomas JM, Xue F, Liu J, Kong L, Voulalas P, Hassan HE, Park JS, MacKerell AD Jr, Smith WW (2014) Novel LRRK2 GTP-binding inhibitors reduced degeneration in Parkinson’s disease cell and mouse models. Hum Mol Genet 23(23):6212–6222. doi:10.1093/hmg/ddu341

    Article  CAS  PubMed  Google Scholar 

  74. Li T, He X, Thomas JM, Yang D, Zhong S, Xue F, Smith WW (2015) A novel GTP-binding inhibitor, FX2149, attenuates LRRK2 toxicity in Parkinson’s disease models. PLoS One 10(3), e0122461. doi:10.1371/journal.pone.0122461

    Article  PubMed  PubMed Central  Google Scholar 

  75. 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

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors are grateful for funding support from the National Institutes of Health (R01 NS091719), the Swiss National Science Foundation (grant no. 31003A_144063), and the Van Andel Research Institute.

Conflict of Interest

The author declares no conflicts of interest.

Author information

Authors and Affiliations

  1. Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Ave NE, Grand Rapids, MI, 49503, USA

    An Phu Tran Nguyen & Darren J. Moore

Authors
  1. An Phu Tran Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Darren J. Moore
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Darren J. Moore .

Editor information

Editors and Affiliations

  1. Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens, Greece

    Hardy J. Rideout

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Nguyen, A.P.T., Moore, D.J. (2017). Understanding the GTPase Activity of LRRK2: Regulation, Function, and Neurotoxicity. In: Rideout, H. (eds) Leucine-Rich Repeat Kinase 2 (LRRK2). Advances in Neurobiology, vol 14. Springer, Cham. https://doi.org/10.1007/978-3-319-49969-7_4

Download citation

Publish with us

Policies and ethics

Search

Navigation