1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Biochemistry
  4. Volume 93, 2024
  5. Article

Annual Review of Biochemistry

Volume 93, 2024

Leucine-Rich Repeat Kinases

Abstract

Activating mutations in leucine-rich repeat kinase 2 (LRRK2) represent the most common cause of monogenic Parkinson's disease. LRRK2 is a large multidomain protein kinase that phosphorylates a specific subset of the ∼65 human Rab GTPases, which are master regulators of the secretory and endocytic pathways. After phosphorylation by LRRK2, Rabs lose the capacity to bind cognate effector proteins and guanine nucleotide exchange factors. Moreover, the phosphorylated Rabs cannot interact with their cognate prenyl-binding retrieval proteins (also known as guanine nucleotide dissociation inhibitors) and, thus, they become trapped on membrane surfaces. Instead, they gain the capacity to bind phospho-Rab-specific effector proteins, such as RILPL1, with resulting pathological consequences. Rab proteins also act upstream of LRRK2 by controlling its activation and recruitment onto membranes. LRRK2 signaling is counteracted by the phosphoprotein phosphatase PPM1H, which selectively dephosphorylates phospho-Rab proteins. We present here our current understanding of the structure, biochemical properties, and cell biology of LRRK2 and its related paralog LRRK1 and discuss how this information guides the generation of LRRK2 inhibitors for the potential benefit of patients.

Keyword(s): Crohn's disease, lysosomal stress, neurodegeneration, Parkinson's disease, PPM1H phosphatase, Rab GTPases
Loading

Article metrics loading...

/content/journals/10.1146/annurev-biochem-030122-051144
2024-08-02
2025-04-22
Loading full text...

Full text loading...

/deliver/fulltext/biochem/93/1/annurev-biochem-030122-051144.html?itemId=/content/journals/10.1146/annurev-biochem-030122-051144&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, et al. 2004.. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. . Neuron 44::601–7
     [Crossref] [Google Scholar]
  2. 2.
    Paisan-Ruiz C, Jain S, Evans EW, Gilks WP, Simon J, et al. 2004.. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. . Neuron 44::595–600
     [Crossref] [Google Scholar]
  3. 3.
    Rocha EM, Keeney MT, Di Maio R, De Miranda BR, Greenamyre JT. 2022.. LRRK2 and idiopathic Parkinson's disease. . Trends Neurosci. 45::224–36
     [Crossref] [Google Scholar]
  4. 4.
    Nalls MA, Blauwendraat C, Vallerga CL, Heilbron K, Bandres-Ciga S, et al. 2019.. Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies. . Lancet 18:(12):1091–102
     [Crossref] [Google Scholar]
  5. 5.
    Saunders-Pullman R, Mirelman A, Alcalay RN, Wang C, Ortega RA, et al. 2018.. Progression in the LRRK2-associated Parkinson disease population. . JAMA Neurol. 75::312–19
     [Crossref] [Google Scholar]
  6. 6.
    Trinh J, Schymanski EL, Smajic S, Kasten M, Sammler E, Grünewald A. 2022.. Molecular mechanisms defining penetrance of LRRK2-associated Parkinson's disease. . Med. Gen. 34::103–16
     [Google Scholar]
  7. 7.
    Ou Z, Pan J, Tang S, Duan D, Yu D, et al. 2021.. Global trends in the incidence, prevalence, and years lived with disability of Parkinson's disease in 204 countries/territories from 1990 to 2019. . Front. Public Health 9::776847
     [Crossref] [Google Scholar]
  8. 8.
    West AB, Moore DJ, Biskup S, Bugayenko A, Smith WW, et al. 2005.. Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. . PNAS 102::16842–47
     [Crossref] [Google Scholar]
  9. 9.
    Gloeckner CJ, Kinkl N, Schumacher A, Braun RJ, O'Neill E, et al. 2006.. The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity. . Hum. Mol. Genet. 15::223–32
     [Crossref] [Google Scholar]
  10. 10.
    Jaleel M, Nichols RJ, Deak M, Campbell DG, Gillardon F, et al. 2007.. LRRK2 phosphorylates moesin at threonine-558: characterization of how Parkinson's disease mutants affect kinase activity. . Biochem. J. 405::307–17
     [Crossref] [Google Scholar]
  11. 11.
    Ito G, Katsemonova K, Tonelli F, Lis P, Baptista MA, et al. 2016.. Phos-tag analysis of Rab10 phosphorylation by LRRK2: a powerful assay for assessing kinase function and inhibitors. . Biochem. J. 473::2671–85
     [Crossref] [Google Scholar]
  12. 12.
    Lis P, Burel S, Steger M, Mann M, Brown F, et al. 2018.. Development of phospho-specific Rab protein antibodies to monitor in vivo activity of the LRRK2 Parkinson's disease kinase. . Biochem. J. 475::1–22
     [Crossref] [Google Scholar]
  13. 13.
    Kim JJ, Makarious MB, Bandres-Ciga S, Gibbs JR, Ding J, et al. 2021.. The Parkinson's disease DNA variant browser. . Mov. Disord. 36::1250–58
     [Crossref] [Google Scholar]
  14. 14.
    Kalogeropulou AF, Purlyte E, Tonelli F, Lange SM, Wightman M, et al. 2022.. Impact of 100 LRRK2 variants linked to Parkinson's disease on kinase activity and microtubule binding. . Biochem. J. 479::1759–83
     [Crossref] [Google Scholar]
  15. 15.
    Borsche M, Pratuseviciute N, Schaake S, Hinrichs F, Morel G, et al. 2023.. The new p.F1700L LRRK2 variant causes Parkinson's disease by extensively increasing kinase activity. . Mov. Disord. 38::1105–7
     [Crossref] [Google Scholar]
  16. 16.
    Zhang Y, Sun Q, Yi M, Zhou X, Guo J, et al. 2017.. Genetic analysis of LRRK2 R1628P in Parkinson's disease in Asian populations. . Park. Dis. 2017::8093124
     [Google Scholar]
  17. 17.
    Dzamko N, Deak M, Hentati F, Reith AD, Prescott AR, et al. 2010.. Inhibition of LRRK2 kinase activity leads to dephosphorylation of Ser910/Ser935, disruption of 14-3-3 binding and altered cytoplasmic localization. . Biochem. J. 430::405–13
     [Crossref] [Google Scholar]
  18. 18.
    Chia R, Haddock S, Beilina A, Rudenko IN, Mamais A, et al. 2014.. Phosphorylation of LRRK2 by casein kinase 1α regulates trans-Golgi clustering via differential interaction with ARHGEF7. . Nat. Commun. 5::5827
     [Crossref] [Google Scholar]
  19. 19.
    Fulcher LJ, Sapkota GP. 2020.. Functions and regulation of the serine/threonine protein kinase CK1 family: moving beyond promiscuity. . Biochem. J. 477::4603–21
     [Crossref] [Google Scholar]
  20. 20.
    Johnson JL, Yaron TM, Huntsman EM, Kerelsky A, Song J, et al. 2023.. An atlas of substrate specificities for the human serine/threonine kinome. . Nature 613::759–66
     [Crossref] [Google Scholar]
  21. 21.
    Nichols J, Dzamko N, Morrice NA, Campbell DG, Deak M, et al. 2010.. 14-3-3 binding to LRRK2 is disrupted by multiple Parkinson's disease associated mutations and regulates cytoplasmic localisation. . Biochem. J. 430::393–404
     [Crossref] [Google Scholar]
  22. 22.
    Doggett EA, Zhao J, Mork CN, Hu D, Nichols RJ. 2011.. Phosphorylation of LRRK2 serines 955 and 973 is disrupted by Parkinson's disease mutations and LRRK2 pharmacological inhibition. . J. Neurochem. 120::37–45
     [Crossref] [Google Scholar]
  23. 23.
    Tasegian A, Singh F, Ganley IG, Reith AD, Alessi DR. 2021.. Impact of Type II LRRK2 inhibitors on signaling and mitophagy. . Biochem. J. 478::3555–73
     [Crossref] [Google Scholar]
  24. 24.
    Sheng Z, Zhang S, Bustos D, Kleinheinz T, Le Pichon CE, et al. 2012.. Ser1292 autophosphorylation is an indicator of LRRK2 kinase activity and contributes to the cellular effects of PD mutations. . Sci. Transl. Med. 4::164ra61
     [Crossref] [Google Scholar]
  25. 25.
    Kluss JH, Conti MM, Kaganovich A, Beilina A, Melrose HL, et al. 2018.. Detection of endogenous S1292 LRRK2 autophosphorylation in mouse tissue as a readout for kinase activity. . npj Park. Dis. 4::13
     [Crossref] [Google Scholar]
  26. 26.
    Deniston CK, Salogiannis J, Mathea S, Snead DM, Lahiri I, et al. 2020.. Structure of LRRK2 in Parkinson's disease and model for microtubule interaction. . Nature 588::344–49
     [Crossref] [Google Scholar]
  27. 27.
    Myasnikov A, Zhu H, Hixson P, Xie B, Yu K, et al. 2021.. Structural analysis of the full-length human LRRK2. . Cell 184::3519–27.e10
     [Crossref] [Google Scholar]
  28. 28.
    Leschziner AE, Murillo MS, Suarez AV, Dederer V, Chatterjee D, et al. 2023.. Inhibition of Parkinson's disease-related LRRK2 by type-I and type-II kinase inhibitors: activity and structures. . Sci. Adv. 9(48):eadk6191
     [Google Scholar]
  29. 29.
    Zhang P, Fan Y, Ru H, Wang L, Magupalli VG, et al. 2019.. Crystal structure of the WD40 domain dimer of LRRK2. . PNAS 116::1579–84
     [Crossref] [Google Scholar]
  30. 30.
    Taylor SS, Kornev AP. 2011.. Protein kinases: evolution of dynamic regulatory proteins. . Trends Biochem. Sci. 36::65–77
     [Crossref] [Google Scholar]
  31. 31.
    Taylor SS, Meharena HS, Kornev AP. 2019.. Evolution of a dynamic molecular switch. . IUBMB Life 71::672–84
     [Crossref] [Google Scholar]
  32. 32.
    Jumper J, Evans R, Pritzel A, Green T, Figurnov M, et al. 2021.. Highly accurate protein structure prediction with AlphaFold. . Nature 596::583–89
     [Crossref] [Google Scholar]
  33. 33.
    Kett LR, Boassa D, Ho CC, Rideout HJ, Hu J, et al. 2012.. LRRK2 Parkinson disease mutations enhance its microtubule association. . Hum. Mol. Genet. 21::890–99
     [Crossref] [Google Scholar]
  34. 34.
    Watanabe R, Buschauer R, Böhning J, Audagnotto M, Lasker K, et al. 2020.. The in situ structure of Parkinson's disease-linked LRRK2. . Cell 182::1508–18
     [Crossref] [Google Scholar]
  35. 35.
    Fell MJ, Mirescu C, Basu K, Cheewatrakoolpong B, DeMong DE, et al. 2015.. MLi-2, a potent, selective, and centrally active compound for exploring the therapeutic potential and safety of LRRK2 kinase inhibition. . J. Pharmacol. Exp. Ther. 355::397–409
     [Crossref] [Google Scholar]
  36. 36.
    Snead DM, Matyszewski M, Dickey AM, Lin YX, Leschziner AE, Reck-Peterson SL. 2022.. Structural basis for Parkinson's disease-linked LRRK2’s binding to microtubules. . Nat. Struct. Mol. Biol. 29::1196–207
     [Crossref] [Google Scholar]
  37. 37.
    Kalogeropulou AF, Freemantle JB, Lis P, Vides EG, Polinski NK, Alessi DR. 2020.. Endogenous Rab29 does not impact basal or stimulated LRRK2 pathway activity. . Biochem. J. 477::4397–423
     [Crossref] [Google Scholar]
  38. 38.
    Greggio E, Zambrano I, Kaganovich A, Beilina A, Taymans J-M, et al. 2008.. The Parkinson disease-associated leucine-rich repeat kinase 2 (LRRK2) is a dimer that undergoes intramolecular autophosphorylation. . J. Biol. Chem. 283::16906–14
     [Crossref] [Google Scholar]
  39. 39.
    Sen S, Webber PJ, West AB. 2009.. Dependence of leucine-rich repeat kinase 2 (LRRK2) kinase activity on dimerization. . J. Biol. Chem. 284::36346–56
     [Crossref] [Google Scholar]
  40. 40.
    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::5511–23
     [Crossref] [Google Scholar]
  41. 41.
    Zhu H, Tonelli F, Turk M, Prescott A, Alessi DR, Sun J. 2022.. Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2. . Science 382(6677):140411
     [Google Scholar]
  42. 42.
    McGrath E, Waschbüsch D, Baker BM, Khan AR. 2019.. LRRK2 binds to the Rab32 subfamily in a GTP-dependent manner via its armadillo domain. . Small GTPases 12:(2):133–146
     [Crossref] [Google Scholar]
  43. 43.
    Vides EG, Adhikari A, Chiang CY, Lis P, Purlyte E, et al. 2022.. A feed-forward pathway drives LRRK2 kinase membrane recruitment and activation. . eLife 11::e79771
     [Crossref] [Google Scholar]
  44. 44.
    Steger M, Tonelli F, Ito G, Davies P, Trost M, et al. 2016.. Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases. . eLife 5::e12813
     [Crossref] [Google Scholar]
  45. 45.
    Steger M, Diez F, Dhekne HS, Lis P, Nirujogi RS, et al. 2017.. Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation establishes a connection to ciliogenesis. . eLife 6::e31012
     [Crossref] [Google Scholar]
  46. 46.
    Martin I, Kim JW, Lee BD, Kang HC, Xu J-C, et al. 2014.. Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease. . Cell 157::472–85
     [Crossref] [Google Scholar]
  47. 47.
    Price A, Manzoni C, Cookson MR, Lewis PA. 2018.. The LRRK2 signalling system. . Cell Tissue Res. 373::39–50
     [Crossref] [Google Scholar]
  48. 48.
    Stenmark H. 2009.. Rab GTPases as coordinators of vesicle traffic. . Nat. Rev. Mol. Cell Biol. 10::513–25
     [Crossref] [Google Scholar]
  49. 49.
    Pfeffer SR. 2017.. Rab GTPases: master regulators that establish the secretory and endocytic pathways. . Mol. Biol. Cell 28::712–15
     [Crossref] [Google Scholar]
  50. 50.
    Homma Y, Hiragi S, Fukuda M. 2021.. Rab family of small GTPases: an updated view on their regulation and functions. . FEBS J. 288::36–55
     [Crossref] [Google Scholar]
  51. 51.
    Pfeffer SR. 2023.. LRRK2 phosphorylation of Rab GTPases in Parkinson's disease. . FEBS Lett. 597::811–18
     [Crossref] [Google Scholar]
  52. 52.
    Lamber EP, Siedenburg AC, Barr FA. 2019.. Rab regulation by GEFs and GAPs during membrane traffic. . Curr. Opin. Cell Biol. 59::34–39
     [Crossref] [Google Scholar]
  53. 53.
    Nirujogi RS, Tonelli F, Taylor M, Lis P, Zimprich A, et al. 2021.. Development of a multiplexed targeted mass spectrometry assay for LRRK2-phosphorylated Rabs and Ser910/Ser935 biomarker sites. . Biochem. J. 478::299–326
     [Crossref] [Google Scholar]
  54. 54.
    Karayel O, Tonelli F, Virreira Winter S, Geyer PE, Fan Y, et al. 2020.. Accurate MS-based Rab10 phosphorylation stoichiometry determination as readout for LRRK2 activity in Parkinson's disease. . Mol. Cell Proteom. 19::1546–60
     [Crossref] [Google Scholar]
  55. 55.
    Fan Y, Howden AJM, Sarhan AR, Lis P, Ito G, et al. 2018.. Interrogating Parkinson's disease LRRK2 kinase pathway activity by assessing Rab10 phosphorylation in human neutrophils. . Biochem. J. 475::23–44
     [Crossref] [Google Scholar]
  56. 56.
    Waschbüsch D, Purlyte E, Pal P, McGrath E, Alessi DR, Khan AR. 2020.. Structural basis for Rab8a recruitment of RILPL2 via LRRK2 phosphorylation of switch 2. . Structure 28::406–17.e6
     [Crossref] [Google Scholar]
  57. 57.
    Dhekne HS, Yanatori I, Vides EG, Sobu Y, Diez F, et al. 2021.. LRRK2-phosphorylated Rab10 sequesters Myosin Va with RILPL2 during ciliogenesis blockade. . Life Sci. Alliance 4::e202101050
     [Crossref] [Google Scholar]
  58. 58.
    Dhekne HS, Yanatori I, Gomez RC, Tonelli F, Diez F, et al. 2018.. A pathway for Parkinson's disease LRRK2 kinase to block primary cilia and Sonic hedgehog signaling in the brain. . eLife 7::e40202
     [Crossref] [Google Scholar]
  59. 59.
    Sobu Y, Wawro PS, Dhekne HS, Yeshaw WM, Pfeffer SR. 2021.. Pathogenic LRRK2 regulates ciliation probability upstream of tau tubulin kinase 2 via Rab10 and RILPL1 proteins. . PNAS 118:(10):e2005894118
     [Crossref] [Google Scholar]
  60. 60.
    Khan SS, Sobu Y, Dhekne HS, Tonelli F, Berndsen K, et al. 2021.. Pathogenic LRRK2 control of primary cilia and Hedgehog signaling in neurons and astrocytes of mouse brain. . eLife 10::e67900
     [Crossref] [Google Scholar]
  61. 61.
    Boecker CA, Goldsmith J, Dou D, Cajka GG, Holzbaur ELF. 2021.. Increased LRRK2 kinase activity alters neuronal autophagy by disrupting the axonal transport of autophagosomes. . Curr. Biol. 31::2140–54.e6
     [Crossref] [Google Scholar]
  62. 62.
    Boecker CA, Holzbaur ELF. 2021.. Hyperactive LRRK2 kinase impairs the trafficking of axonal autophagosomes. . Autophagy 17::2043–45
     [Crossref] [Google Scholar]
  63. 63.
    Fasiczka R, Naaldijk Y, Brahmia B, Hilfiker S. 2023.. Insights into the cellular consequences of LRRK2-mediated Rab protein phosphorylation. . Biochem. Soc. Trans. 51::587–95
     [Crossref] [Google Scholar]
  64. 64.
    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::5511–23
     [Crossref] [Google Scholar]
  65. 65.
    Purlyte E, Dhekne HS, Sarhan AR, Gomez R, Lis P, et al. 2018.. Rab29 activation of the Parkinson's disease-associated LRRK2 kinase. . EMBO J. 37::1–18. Corrigendum. EMBO J. 38::e101237
     [Google Scholar]
  66. 66.
    Simon-Sanchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, et al. 2009.. Genome-wide association study reveals genetic risk underlying Parkinson's disease. . Nat. Genet. 41::1308–12
     [Crossref] [Google Scholar]
  67. 67.
    Liu Z, Bryant N, Kumaran R, Beilina A, Abeliovich A, et al. 2018.. LRRK2 phosphorylates membrane-bound Rabs and is activated by GTP-bound Rab7L1 to promote recruitment to the trans-Golgi network. . Hum. Mol. Genet. 27::385–95
     [Crossref] [Google Scholar]
  68. 68.
    Gomez RC, Wawro P, Lis P, Alessi DR, Pfeffer SR. 2019.. Membrane association but not identity is required for LRRK2 activation and phosphorylation of Rab GTPases. . J. Cell Biol. 218:(12):415770
     [Crossref] [Google Scholar]
  69. 69.
    Kuwahara T, Funakawa K, Komori T, Sakurai M, Yoshii G, et al. 2020.. Roles of lysosomotropic agents on LRRK2 activation and Rab10 phosphorylation. . Neurobiol. Dis. 145::105081
     [Crossref] [Google Scholar]
  70. 70.
    Eguchi T, Kuwahara T, Sakurai M, Komori T, Fujimoto T, et al. 2018.. LRRK2 and its substrate Rab GTPases are sequentially targeted onto stressed lysosomes and maintain their homeostasis. . PNAS 115::E9115–24
     [Crossref] [Google Scholar]
  71. 71.
    Bonet-Ponce L, Beilina A, Williamson CD, Lindberg E, Kluss JH, et al. 2020.. LRRK2 mediates tubulation and vesicle sorting from lysosomes. . Sci. Adv. 6::eabb2454
     [Crossref] [Google Scholar]
  72. 72.
    Unapanta A, Shavarebi F, Porath J, Shen Y, Balen C, et al. 2023.. Endogenous Rab38 regulates LRRK2’s membrane recruitment and substrate Rab phosphorylation in melanocytes. . J. Biol. Chem. 299:(10):105192
     [Crossref] [Google Scholar]
  73. 73.
    Dhekne HS, Tonelli F, Yeshaw WM, Chiang CY, Limouse C, et al. 2023.. Genome-wide screen reveals Rab12 GTPase as a critical activator of pathogenic LRRK2 kinase. . bioRxiv 2023.02.17.529028. https://doi.org/10.1101/2023.02.17.529028
  74. 74.
    Bondar VV, Wang X, Davis OB, Maloney MT, Agam M, et al. 2023.. Rab12 regulates LRRK2 activity by promoting its localization to lysosomes. . bioRxiv 2023.02.21.529466. https://doi.org/10.1101/2023.02.21.529466
  75. 75.
    Alessi DR, Sammler E. 2018.. LRRK2 kinase in Parkinson's disease. . Science 360::36–37
     [Crossref] [Google Scholar]
  76. 76.
    Jennings D, Huntwork-Rodriguez S, Henry AG, Sasaki JC, Meisner R, et al. 2022.. Preclinical and clinical evaluation of the LRRK2 inhibitor DNL201 for Parkinson's disease. . Sci. Transl. Med. 14::eabj2658
     [Crossref] [Google Scholar]
  77. 77.
    Tolosa E, Vila M, Klein C, Rascol O. 2020.. LRRK2 in Parkinson disease: challenges of clinical trials. . Nat. Rev. Neurol. 16::97–107
     [Crossref] [Google Scholar]
  78. 78.
    Ferguson FM, Gray NS. 2018.. Kinase inhibitors: the road ahead. . Nat. Rev. Drug Discov. 17::353–77
     [Crossref] [Google Scholar]
  79. 79.
    Li X, Wang QJ, Pan N, Lee S, Zhao Y, et al. 2011.. Phosphorylation-dependent 14-3-3 binding to LRRK2 is impaired by common mutations of familial Parkinson's disease. . PLOS ONE 6::e17153
     [Crossref] [Google Scholar]
  80. 80.
    Lavalley NJ, Slone SR, Ding H, West AB, Yacoubian TA. 2016.. 14-3-3 Proteins regulate mutant LRRK2 kinase activity and neurite shortening. . Hum. Mol. Genet. 25::109–22
     [Crossref] [Google Scholar]
  81. 81.
    Schmidt SH, Knape MJ, Boassa D, Mumdey N, Kornev AP, et al. 2019.. The dynamic switch mechanism that leads to activation of LRRK2 is embedded in the DFGψ motif in the kinase domain. . PNAS 116::14979–88
     [Crossref] [Google Scholar]
  82. 82.
    Baptista MA, Dave KD, Frasier MA, Sherer TB, Greeley M, et al. 2013.. Loss of leucine-rich repeat kinase 2 (LRRK2) in rats leads to progressive abnormal phenotypes in peripheral organs. . PLOS ONE 8::e80705
     [Crossref] [Google Scholar]
  83. 83.
    Baptista MAS, Merchant K, Barrett T, Bhargava S, Bryce DK, et al. 2020.. LRRK2 inhibitors induce reversible changes in nonhuman primate lungs without measurable pulmonary deficits. . Sci. Transl. Med. 12::eaav0820
     [Crossref] [Google Scholar]
  84. 84.
    Miller G, Kuruvilla S, Jacob B, Bakthavatchalu V, LaFranco-Scheuch L, et al. 2023.. Effects of LRRK2 inhibitors in nonhuman primates. . Toxicol. Pathol. 51::232–45
     [Crossref] [Google Scholar]
  85. 85.
    Whiffin N, Armean IM, Kleinman A, Marshall JL, Minikel EV, et al. 2020.. The effect of LRRK2 loss-of-function variants in humans. . Nat. Med. 26::869–77
     [Crossref] [Google Scholar]
  86. 86.
    Liu Y, Gray NS. 2006.. Rational design of inhibitors that bind to inactive kinase conformations. . Nat. Chem. Biol. 2::358–64
     [Crossref] [Google Scholar]
  87. 87.
    Weng JH, Aoto PC, Lorenz R, Wu J, Schmidt SH, et al. 2022.. LRRK2 dynamics analysis identifies allosteric control of the crosstalk between its catalytic domains. . PLOS Biol. 20::e3001427
     [Crossref] [Google Scholar]
  88. 88.
    Berndsen K, Lis P, Yeshaw WM, Wawro PS, Nirujogi RS, et al. 2019.. PPM1H phosphatase counteracts LRRK2 signaling by selectively dephosphorylating Rab proteins. . eLife 8::e50416
     [Crossref] [Google Scholar]
  89. 89.
    Flint AJ, Tiganis T, Barford D, Tonks NK. 1997.. Development of “substrate-trapping” mutants to identify physiological substrates of protein tyrosine phosphatases. . PNAS 94::1680–85
     [Crossref] [Google Scholar]
  90. 90.
    Debnath S, Kosek D, Tagad HD, Durell SR, Appella DH, et al. 2018.. A trapped human PPM1A–phosphopeptide complex reveals structural features critical for regulation of PPM protein phosphatase activity. . J. Biol. Chem. 293::7993–8008
     [Crossref] [Google Scholar]
  91. 91.
    Waschbusch D, Berndsen K, Lis P, Knebel A, Lam YP, et al. 2021.. Structural basis for the specificity of PPM1H phosphatase for Rab GTPases. . EMBO Rep. 22::e52675
     [Crossref] [Google Scholar]
  92. 92.
    Yeshaw WM, Adhikari A, Chiang CY, Dhekne HS, Wawro PS, Pfeffer SR. 2023.. Localization of PPM1H phosphatase tunes Parkinson's disease-linked LRRK2 kinase-mediated Rab GTPase phosphorylation and ciliogenesis. . PNAS 120(44):e2315171120
     [Google Scholar]
  93. 93.
    Dou D, Smith EM, Evans CS, Boecker CA, Holzbaur ELF. 2023.. Regulatory imbalance between LRRK2 kinase, PPM1H phosphatase, and ARF6 GTPase disrupts the axonal transport of autophagosomes. . Cell Rep. 42::112448
     [Crossref] [Google Scholar]
  94. 94.
    Herbst S, Campbell P, Harvey J, Bernard EM, Papayannopoulos V, et al. 2020.. LRRK2 activation controls the repair of damaged endomembranes in macrophages. . EMBO J. 39::e104494
     [Crossref] [Google Scholar]
  95. 95.
    Uchimoto T, Nohara H, Kamehara R, Iwamura M, Watanabe N, Kobayashi Y. 1999.. Mechanism of apoptosis induced by a lysosomotropic agent, L-Leucyl-L-Leucine methyl ester. . Apoptosis 4::357–62
     [Crossref] [Google Scholar]
  96. 96.
    Bohannon KP, Hanson PI. 2020.. ESCRT puts its thumb on the nanoscale: fixing tiny holes in endolysosomes. . Curr. Opin. Cell Biol. 65::122–30
     [Crossref] [Google Scholar]
  97. 97.
    Skowyra ML, Schlesinger PH, Naismith TV, Hanson PI. 2018.. Triggered recruitment of ESCRT machinery promotes endolysosomal repair. . Science 360::eaar5078
     [Crossref] [Google Scholar]
  98. 98.
    Radulovic M, Schink KO, Wenzel EM, Nahse V, Bongiovanni A, et al. 2018.. ESCRT-mediated lysosome repair precedes lysophagy and promotes cell survival. . EMBO J. 37::e99753
     [Crossref] [Google Scholar]
  99. 99.
    Lopez-Jimenez AT, Cardenal-Munoz E, Leuba F, Gerstenmaier L, Barisch C, et al. 2018.. The ESCRT and autophagy machineries cooperate to repair ESX-1-dependent damage at the Mycobacterium-containing vacuole but have opposite impact on containing the infection. . PLOS Pathog. 14::e1007501
     [Crossref] [Google Scholar]
  100. 100.
    Jia J, Claude-Taupin A, Gu Y, Choi SW, Peters R, et al. 2020.. Galectin-3 coordinates a cellular system for lysosomal repair and removal. . Dev. Cell 52::69–87.e8
     [Crossref] [Google Scholar]
  101. 101.
    Niekamp P, Scharte F, Sokoya T, Vittadello L, Kim Y, et al. 2022.. Ca2+-activated sphingomyelin scrambling and turnover mediate ESCRT-independent lysosomal repair. . Nat. Commun. 13::1875
     [Crossref] [Google Scholar]
  102. 102.
    Tan JX, Finkel T. 2022.. A phosphoinositide signalling pathway mediates rapid lysosomal repair. . Nature 609::815–21
     [Crossref] [Google Scholar]
  103. 103.
    Radulovic M, Wenzel EM, Gilani S, Holland LK, Lystad AH, et al. 2022.. Cholesterol transfer via endoplasmic reticulum contacts mediates lysosome damage repair. . EMBO J. 41::e112677
     [Crossref] [Google Scholar]
  104. 104.
    Dziurdzik SK, Conibear E. 2021.. The Vps13 family of lipid transporters and its role at membrane contact sites. . Int. J. Mol. Sci. 22:(6):2905
     [Crossref] [Google Scholar]
  105. 105.
    Tofaris GK. 2012.. Lysosome-dependent pathways as a unifying theme in Parkinson's disease. . Mov. Disord. 27::1364–69
     [Crossref] [Google Scholar]
  106. 106.
    Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, et al. 2009.. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. . N. Engl. J. Med. 361::1651–61
     [Crossref] [Google Scholar]
  107. 107.
    van Veen S, Martin S, Van den Haute C, Benoy V, Lyons J, et al. 2020.. ATP13A2 deficiency disrupts lysosomal polyamine export. . Nature 578::419–24
     [Crossref] [Google Scholar]
  108. 108.
    Hopfner F, Mueller SH, Szymczak S, Junge O, Tittmann L, et al. 2020.. Rare variants in specific lysosomal genes are associated with Parkinson's disease. . Mov. Disord. 35::1245–48
     [Crossref] [Google Scholar]
  109. 109.
    Madureira M, Connor-Robson N, Wade-Martins R. 2020.. LRRK2: autophagy and lysosomal activity. . Front. Neurosci. 14::498
     [Crossref] [Google Scholar]
  110. 110.
    Singh F, Prescott AR, Rosewell P, Ball G, Reith AD, Ganley IG. 2021.. Pharmacological rescue of impaired mitophagy in Parkinson's disease-related LRRK2 G2019S knock-in mice. . eLife 10::67604
     [Crossref] [Google Scholar]
  111. 111.
    Yadavalli N, Ferguson SM. 2023.. LRRK2 suppresses lysosome degradative activity in macrophages and microglia through MiT-TFE transcription factor inhibition. . PNAS 120::e2303789120
     [Crossref] [Google Scholar]
  112. 112.
    Perera RM, Di Malta C, Ballabio A. 2019.. MiT/TFE family of transcription factors, lysosomes, and cancer. . Annu. Rev. Cancer Biol. 3::203–22
     [Crossref] [Google Scholar]
  113. 113.
    Maloney MT, Wang X, Ghosh R, Andrews SV, Maciuca R, et al. 2022.. LRRK2 kinase activity regulates Parkinson's disease-relevant lipids at the lysosome. . bioRxiv 2022.12.19.521070. https://doi.org/10.1101/2022.12.19.521070
  114. 114.
    Ysselstein D, Nguyen M, Young TJ, Severino A, Schwake M, et al. 2019.. LRRK2 kinase activity regulates lysosomal glucocerebrosidase in neurons derived from Parkinson's disease patients. . Nat. Commun. 10::5570
     [Crossref] [Google Scholar]
  115. 115.
    Cook L, Schulze J, Uhlmann WR, Verbrugge J, Marder K, et al. 2022.. Tools for communicating risk for Parkinson's disease. . npj Park. Dis. 8::164
     [Crossref] [Google Scholar]
  116. 116.
    Alcalay RN, Hsieh F, Tengstrand E, Padmanabhan S, Baptista M, et al. 2020.. Higher urine bis(monoacylglycerol)phosphate levels in LRRK2 G2019S mutation carriers: implications for therapeutic development. . Mov. Disord. 35::134–41
     [Crossref] [Google Scholar]
  117. 117.
    Willett R, Martina JA, Zewe JP, Wills R, Hammond GRV, Puertollano R. 2017.. TFEB regulates lysosomal positioning by modulating TMEM55B expression and JIP4 recruitment to lysosomes. . Nat. Commun. 8::1580
     [Crossref] [Google Scholar]
  118. 118.
    Kumar G, Chawla P, Dhiman N, Chadha S, Sharma S, et al. 2022.. RUFY3 links Arl8b and JIP4-dynein complex to regulate lysosome size and positioning. . Nat. Commun. 13::1540
     [Crossref] [Google Scholar]
  119. 119.
    Zimprich A, Benet-Pages A, Struhal W, Graf E, Eck SH, et al. 2011.. A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. . Am. J. Hum. Genet. 89::168–75
     [Crossref] [Google Scholar]
  120. 120.
    Vilarino-Guell C, Wider C, Ross OA, Dachsel JC, Kachergus JM, et al. 2011.. VPS35 mutations in Parkinson disease. . Am. J. Hum. Genet. 89::162–67
     [Crossref] [Google Scholar]
  121. 121.
    Mir R, Tonelli F, Lis P, Macartney T, Polinski NK, et al. 2018.. The Parkinson's disease VPS35[D620N] mutation enhances LRRK2-mediated Rab protein phosphorylation in mouse and human. . Biochem. J. 475::1861–83
     [Crossref] [Google Scholar]
  122. 122.
    Kovtun O, Leneva N, Bykov YS, Ariotti N, Teasdale RD, et al. 2018.. Structure of the membrane-assembled retromer coat determined by cryo-electron tomography. . Nature 561::561–64
     [Crossref] [Google Scholar]
  123. 123.
    McGough IJ, Steinberg F, Jia D, Barbuti PA, McMillan KJ, et al. 2014.. Retromer binding to FAM21 and the WASH complex is perturbed by the Parkinson disease-linked VPS35(D620N) mutation. . Curr. Biol. 24::1670–76
     [Crossref] [Google Scholar]
  124. 124.
    Zavodszky E, Seaman MN, Moreau K, Jimenez-Sanchez M, Breusegem SY, et al. 2014.. Mutation in VPS35 associated with Parkinson's disease impairs WASH complex association and inhibits autophagy. . Nat. Commun. 5::3828
     [Crossref] [Google Scholar]
  125. 125.
    Follett J, Norwood SJ, Hamilton NA, Mohan M, Kovtun O, et al. 2014.. The Vps35 D620N mutation linked to Parkinson's disease disrupts the cargo sorting function of retromer. . Traffic 15::230–44
     [Crossref] [Google Scholar]
  126. 126.
    Pal P, Taylor M, Lam PY, Tonelli F, Hecht CA, et al. 2023.. Parkinson's VP535[D620N] mutation induces LRRK2 mediated lysosomal association of RILPL1 and TMEM55B. . bioRxiv 2023.06.07.544051. https://doi.org/10.1101/2023.06.07.544051
  127. 127.
    Hui KY, Fernandez-Hernandez H, Hu J, Schaffner A, Pankratz N, et al. 2018.. Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease. . Sci. Transl. Med. 10::eaai7795
     [Crossref] [Google Scholar]
  128. 128.
    Lake J, Reed X, Langston RG, Nalls MA, Gan-Or Z, et al. 2022.. Coding and noncoding variation in LRRK2 and Parkinson's disease risk. . Mov. Disord. 37::95–105
     [Crossref] [Google Scholar]
  129. 129.
    Nixon-Abell J, Berwick DC, Granno S, Spain VA, Blackstone C, Harvey K. 2016.. Protective LRRK2 R1398H variant enhances GTPase and Wnt signaling activity. . Front. Mol. Neurosci. 9::18
     [Crossref] [Google Scholar]
  130. 130.
    Gardet A, Benita Y, Li C, Sands BE, Ballester I, et al. 2011.. LRRK2 is involved in the IFN-γ response and host response to pathogens. . J. Immunol. 185::5577–85
     [Crossref] [Google Scholar]
  131. 131.
    Herrick MK, Tansey MG. 2021.. Is LRRK2 the missing link between inflammatory bowel disease and Parkinson's disease?. npj Park. Dis. 7::26
     [Crossref] [Google Scholar]
  132. 132.
    Zhang FR, Huang W, Chen SM, Sun LD, Liu H, et al. 2009.. Genomewide association study of leprosy. . N. Engl. J. Med. 361::2609–18
     [Crossref] [Google Scholar]
  133. 133.
    Wang D, Xu L, Lv L, Su LY, Fan Y, et al. 2015.. Association of the LRRK2 genetic polymorphisms with leprosy in Han Chinese from Southwest China. . Genes Immun. 16::112–19
     [Crossref] [Google Scholar]
  134. 134.
    Fava VM, Manry J, Cobat A, Orlova M, Van Thuc N, et al. 2016.. A missense LRRK2 variant is a risk factor for excessive inflammatory responses in leprosy. . PLOS Negl. Trop. Dis. 10::e0004412
     [Crossref] [Google Scholar]
  135. 135.
    Hartlova A, Herbst S, Peltier J, Rodgers A, Bilkei-Gorzo O, et al. 2018.. LRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages. . EMBO J. 37::e98694
     [Crossref] [Google Scholar]
  136. 136.
    Wang Z, Arat S, Magid-Slav M, Brown JR. 2018.. Meta-analysis of human gene expression in response to Mycobacterium tuberculosis infection reveals potential therapeutic targets. . BMC Syst. Biol. 12::3
     [Crossref] [Google Scholar]
  137. 137.
    Magne J, Green DR. 2022.. LC3-associated endocytosis and the functions of Rubicon and ATG16L1. . Sci. Adv. 8::eabo5600
     [Crossref] [Google Scholar]
  138. 138.
    Iida A, Xing W, Docx MK, Nakashima T, Wang Z, et al. 2016.. Identification of biallelic LRRK1 mutations in osteosclerotic metaphyseal dysplasia and evidence for locus heterogeneity. . J. Med. Genet. 53::568–74
     [Crossref] [Google Scholar]
  139. 139.
    Hanafusa H, Yagi T, Ikeda H, Hisamoto N, Nishioka T, et al. 2019.. LRRK1 phosphorylation of Rab7 at S72 links trafficking of EGFR-containing endosomes to its effector RILP. . J. Cell Sci. 132::jcs228809
     [Crossref] [Google Scholar]
  140. 140.
    Malik AU, Karapetsas A, Nirujogi RS, Mathea S, Chatterjee D, et al. 2021.. Deciphering the LRRK code: LRRK1 and LRRK2 phosphorylate distinct Rab proteins and are regulated by diverse mechanisms. . Biochem. J. 478::553–78
     [Crossref] [Google Scholar]
  141. 141.
    Ishikawa K, Nara A, Matsumoto K, Hanafusa H. 2012.. EGFR-dependent phosphorylation of leucine-rich repeat kinase LRRK1 is important for proper endosomal trafficking of EGFR. . Mol. Biol. Cell 23::1294–306
     [Crossref] [Google Scholar]
  142. 142.
    Metcalfe RD, Martinez Fiesco JA, Bonet-Ponce L, Kluss JH, Cookson MR, Zhang P. 2023.. Structure and regulation of full-length human leucine-rich repeat kinase 1. . Nat. Comm. 14::4797
     [Crossref] [Google Scholar]
  143. 143.
    Tudorica DA, Basak B, Cordova AP, Khuu G, Rose K, et al. 2023.. A RAB7A phosphoswitch coordinates rubicon homology protein regulation of PINK1/Parkin-dependent mitophagy. . bioRxiv 2023.08.28.555228. https://doi.org/10.1101/2023.08.28.555228
  144. 144.
    Reimer JM, Dickey AM, Lin YX, Abrisch RG, Mathea S, et al. 2022.. Structure of LRRK1 and mechanisms of autoinhibition and activation. . Nat. Struct. Mol. Biol. 30::1735–45
     [Crossref] [Google Scholar]
  145. 145.
    Malik AU, Karapetsas A, Nirujogi RS, Chatterjee D, Phung TK, et al. 2022.. PKC isoforms activate LRRK1 kinase by phosphorylating conserved residues (Ser1064, Ser1074 and Thr1075) within the CORB GTPase domain. . Biochem. J. 479::1941–65
     [Crossref] [Google Scholar]
  146. 146.
    Marin I. 2008.. Ancient origin of the Parkinson disease gene LRRK2. . J. Mol. Evol. 67::41–50
     [Crossref] [Google Scholar]
  147. 147.
    Yao C, El Khoury R, Wang W, Byrd TA, Pehek EA, et al. 2010.. LRRK2-mediated neurodegeneration and dysfunction of dopaminergic neurons in a Caenorhabditis elegans model of Parkinson's disease. . Neurobiol. Dis. 40::73–81
     [Crossref] [Google Scholar]
  148. 148.
    Liu Z, Wang X, Yu Y, Li X, Wang T, et al. 2008.. A Drosophila model for LRRK2-linked parkinsonism. . PNAS 105::2693–98
     [Crossref] [Google Scholar]
  149. 149.
    van Egmond WN, van Haastert PJ. 2010.. Characterization of the Roco protein family in Dictyostelium discoideum. . Eukaryot. Cell 9::751–61
     [Crossref] [Google Scholar]
  150. 150.
    Marin I. 2006.. The Parkinson disease gene LRRK2: evolutionary and structural insights. . Mol. Biol. Evol. 23::2423–33
     [Crossref] [Google Scholar]
/content/journals/10.1146/annurev-biochem-030122-051144
Loading
Leucine-Rich Repeat Kinases
Annual Review of Biochemistry 93, 261 (2024); https://doi.org/10.1146/annurev-biochem-030122-051144
/content/journals/10.1146/annurev-biochem-030122-051144
/content/journals/10.1146/annurev-biochem-030122-051144
Loading

Data & Media loading...

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error