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Cited by 153Parkinson's Disease Mechanisms and TreatmentsNuclear Receptors and SignalingProtein Kinase Regulation and GTPase Signaling

Perspective on the current state of the LRRK2 field

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Taymans, Jean-Marc, Fell, Matt, Greenamyre, Tim, Hirst, Warren D., Mamais, Adamantios, Padmanabhan, Shalini, Peter, Inga, Rideout, Hardy +1 more·2023·npj Parkinson's Disease
DOI 10.1038/s41531-023-00544-7PMC PMC10314919
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Abstract

Almost 2 decades after linking LRRK2 to Parkinson’s disease, a vibrant research field has developed around the study of this gene and its protein product. Recent studies have begun to elucidate molecular structures of LRRK2 and its complexes, and our understanding of LRRK2 has continued to grow, affirming decisions made years ago to therapeutically target this enzyme for PD. Markers of LRRK2 activity, with potential to monitor disease progression or treatment efficacy, are also under development. Interestingly, there is a growing understanding of the role of LRRK2 outside of the central nervous system in peripheral tissues such as gut and immune cells that may also contribute to LRRK2 mediated pathology. In this perspective, our goal is to take stock of LRRK2 research by discussing the current state of knowledge and critical open questions in the field.

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  • LRRK2 mutations are associated with familial and sporadic PD, and LRRK2 is a promising therapeutic target for PD.

    “LRRK2 mutations are associated with familial and sporadic PD, and LRRK2 is a promising therapeutic target for PD167.”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [167]

    The Introduction reports LRRK2 mutations that segregate with PD in families, and “LRRK2 as a therapeutic target” describes it as a PD target while noting that clinical validation remains pending. For sporadic or idiopathic PD, the paper discusses common variants near LRRK2 and possible involvement of wild-type LRRK2, rather than establishing that LRRK2 mutations are associated with sporadic PD. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Leucine-rich repeat kinase 2 (LRRK2) is the most common gene linked to Parkinson's disease.

    “Leucine-rich repeat kinase 2 (LRRK2) is the most common gene linked to PD.”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [167]

    The Introduction says LRRK2 mutations are relatively common compared with mutations in other PD genes and identifies LRRK2 as a PD risk locus. It does not establish the stronger claim that LRRK2 is the most common gene linked to PD. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

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  1. [1]Funayama M A new locus for Parkinson’s disease (PARK8) maps to chromosome 12p11.2-q13.1 Ann. Neurol. 2002 51 296 301 10.1002/ana.10113 11891824 · DOI
  2. [2]Paisán-Ruíz C Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease Neuron 2004 44 595 600 10.1016/j.neuron.2004.10.023 15541308 · DOI
  3. [3]Zimprich A Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology Neuron 2004 44 601 607 10.1016/j.neuron.2004.11.005 15541309 · DOI
  4. [4]Bosgraaf L Van Haastert PJM Roc, a Ras/GTPase domain in complex proteins Biochim. Biophys. Acta 2003 1643 5 10 10.1016/j.bbamcr.2003.08.008 14654223 · DOI
  5. [5]West AB Parkinson’s disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity Proc. Natl Acad. Sci. USA 2005 102 16842 16847 10.1073/pnas.0507360102 16269541 PMC1283829 · DOI · Paper page
  6. [6]Greggio E Kinase activity is required for the toxic effects of mutant LRRK2/dardarin Neurobiol. Dis. 2006 23 329 341 10.1016/j.nbd.2006.04.001 16750377 · DOI
  7. [7]Nichols RJ Substrate specificity and inhibitors of LRRK2, a protein kinase mutated in Parkinson’s disease Biochem. J. 2009 424 47 60 10.1042/BJ20091035 19740074 PMC3759966 · DOI
  8. [8]Paisán-Ruiz C Lewis PA Singleton AB LRRK2: cause, risk, and mechanism J. Parkinson’s Dis. 2013 3 85 103 10.3233/JPD-130192 23938341 PMC3952583 · DOI
  9. [9]Satake W Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson’s disease Nat. Genet. 2009 41 1303 1307 10.1038/ng.485 19915576 · DOI
  10. [10]Simón-Sánchez J Genome-wide association study reveals genetic risk underlying Parkinson’s disease Nat. Genet. 2009 41 1308 1312 10.1038/ng.487 19915575 PMC2787725 · DOI
  11. [11]Seegobin SP Progress in LRRK2-associated parkinson’s disease animal models Front. Neurosci. 2020 14 674 10.3389/fnins.2020.00674 32765209 PMC7381130 · DOI
  12. [12]Daniëls V Baekelandt V Taymans J-M On the road to leucine-rich repeat kinase 2 signalling: evidence from cellular and in vivo studies Neuro-Signals 2011 19 1 15 10.1159/000324488 21430363 · DOI
  13. [13]Kett LR LRRK2 Parkinson disease mutations enhance its microtubule association Hum. Mol. Genet. 2012 21 890 899 10.1093/hmg/ddr526 22080837 PMC3263991 · DOI
  14. [14]Parisiadou L Phosphorylation of ezrin/radixin/moesin proteins by LRRK2 promotes the rearrangement of actin cytoskeleton in neuronal morphogenesis J. Neurosci. 2009 29 13971 13980 10.1523/JNEUROSCI.3799-09.2009 19890007 PMC2807632 · DOI
  15. [15]Drolet RE Sanders JM Kern JT Leucine-rich repeat kinase 2 (LRRK2) cellular biology: a review of recent advances in identifying physiological substrates and cellular functions J. Neurogenet. 2011 25 140 151 10.3109/01677063.2011.627072 22077787 · DOI
  16. [16]Erb ML Moore DJ LRRK2 and the endolysosomal system in Parkinson’s disease J. Parkinson’s Dis. 2020 10 1271 1291 10.3233/JPD-202138 33044192 PMC7677880 · DOI
  17. [17]Kluss JH Bonet-Ponce L Lewis PA Cookson MR Directing LRRK2 to membranes of the endolysosomal pathway triggers RAB phosphorylation and JIP4 recruitment Neurobiol. Dis. 2022 170 105769 10.1016/j.nbd.2022.105769 35580815 PMC9665168 · DOI
  18. [18]Bonet-Ponce, L. & Cookson, M. R. LRRK2 recruitment, activity, and function in organelles. FEBS J.10.1111/febs.16099 (2021). PMC8744135 34196120 · DOI
  19. [19]Steger M Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases eLife 2016 5 1 28 10.7554/eLife.12813 PMC4769169 26824392 · DOI
  20. [20]Bonet-Ponce, L. & Cookson, M. R. LRRK2 recruitment, activity, and function in organelles. FEBS J.10.1111/febs.16099 (2021). PMC8744135 34196120 · DOI
  21. [21]Nichols RJ 14-3-3 binding to LRRK2 is disrupted by multiple Parkinson’s disease-associated mutations and regulates cytoplasmic localization Biochem. J. 2010 430 393 404 10.1042/BJ20100483 20642453 PMC2932554 · DOI
  22. [22]Marchand A Drouyer M Sarchione A Chartier-Harlin MC Taymans JM LRRK2 phosphorylation, more than an Epiphenomenon Front. Neurosci. 2020 14 4646 4656.e4 10.3389/fnins.2020.00527 PMC7308437 32612495 · DOI
  23. [23]Dzamko N 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. 2010 430 405 413 10.1042/BJ20100784 20659021 PMC3631100 · DOI
  24. [25]Xu E Pathological α-synuclein recruits LRRK2 expressing pro-inflammatory monocytes to the brain Mol. Neurodegener. 2022 17 7 10.1186/s13024-021-00509-5 35012605 PMC8751347 · DOI
  25. [26]Tsafaras G Baekelandt V The role of LRRK2 in the periphery: link with Parkinson’s disease and inflammatory diseases Neurobiol. Dis. 2022 172 105806 10.1016/j.nbd.2022.105806 35781002 · DOI
  26. [27]Wallings RL Herrick MK Tansey MG LRRK2 at the interface between peripheral and central immune function in Parkinson’s Front. Neurosci. 2020 14 4646 4656.e4 10.3389/fnins.2020.00443 PMC7253584 32508566 · DOI
  27. [28]Tansey, M. G. et al. Inflammation and immune dysfunction in Parkinson disease. Nat. Rev. Immunol.22, 657–673 (2022). PMC8895080 35246670
  28. [29]Herrick MK Tansey MG Is LRRK2 the missing link between inflammatory bowel disease and Parkinson’s disease? NPJ Parkinsons Dis. 2021 7 26 10.1038/s41531-021-00170-1 33750819 PMC7943592 · DOI
  29. [30]Deng X Characterization of a selective inhibitor of the Parkinson’s disease kinase LRRK2 Nat. Chem. Biol. 2011 7 203 205 10.1038/nchembio.538 21378983 PMC3287420 · DOI
  30. [31]Reith AD GSK2578215A; a potent and highly selective 2-arylmethyloxy-5-substitutent-N-arylbenzamide LRRK2 kinase inhibitor Bioorg. Med. Chem. Lett. 2012 22 5625 5629 10.1016/j.bmcl.2012.06.104 22863203 PMC4208292 · DOI
  31. [32]Estrada AA Discovery of highly potent, selective, and brain-penetrant aminopyrazole leucine-rich repeat kinase 2 (LRRK2) small molecule inhibitors J. Med. Chem. 2014 57 921 936 10.1021/jm401654j 24354345 · DOI
  32. [33]Henderson, J. L. et al. Discovery and preclinical profiling of 3-[4-(morpholin-4-yl)−7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (PF-06447475), a highly potent, selective, brain penetrant, and in vivo active LRRK2 kinase inhibitor. J. Med. Chem.58, 419–432 (2015). 25353650
  33. [34]Baptista MAS LRRK2 inhibitors induce reversible changes in nonhuman primate lungs without measurable pulmonary deficits Sci. Transl. Med. 2020 12 eaav0820 10.1126/scitranslmed.aav0820 32321864 · DOI
  34. [35]Fell MJ MLi-2, a potent, selective, and centrally active compound for exploring the therapeutic potential and safety of LRRK2 kinase inhibition J. Pharmacol. Exp. Ther. 2015 355 397 409 10.1124/jpet.115.227587 26407721 · DOI
  35. [36]Jennings D Preclinical and clinical evaluation of the LRRK2 inhibitor DNL201 for Parkinson’s disease Sci. Transl. Med. 2022 14 eabj2658 10.1126/scitranslmed.abj2658 35675433 · DOI
  36. [37]Zhao HT LRRK2 antisense oligonucleotides ameliorate α-synuclein inclusion formation in a Parkinson’s disease mouse model. Mol. Ther. Nucleic Acids 2017 8 508 519 10.1016/j.omtn.2017.08.002 28918051 PMC5573879 · DOI
  37. [38]Beilina A Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease Proc. Natl Acad. Sci. USA 2014 111 2626 2631 10.1073/pnas.1318306111 24510904 PMC3932908 · DOI
  38. [39]Eguchi T LRRK2 and its substrate Rab GTPases are sequentially targeted onto stressed lysosomes and maintain their homeostasis Proc. Natl Acad. Sci. USA 2018 115 E9115 E9124 10.1073/pnas.1812196115 30209220 PMC6166828 · DOI
  39. [40]Madero-Pérez J Parkinson disease-associated mutations in LRRK2 cause centrosomal defects via Rab8a phosphorylation Mol. Neurodegen. 2018 13 4646 4656.e4 10.1186/s13024-018-0235-y PMC5778812 29357897 · DOI
  40. [41]Steger M Systematic proteomic analysis of LRRK2-mediated rab GTPase phosphorylation establishes a connection to ciliogenesis eLife 2017 6 4646 4656.e4 10.7554/eLife.31012 PMC5695910 29125462 · DOI
  41. [43]Mamais A Mutations in LRRK2 linked to Parkinson disease sequester Rab8a to damaged lysosomes and regulate transferrin-mediated iron uptake in microglia PLOS Biol. 2021 19 e3001480 10.1371/journal.pbio.3001480 34914695 PMC8675653 · DOI
  42. [44]Mortiboys H Johansen KK Aasly JO Bandmann O Mitochondrial impairment in patients with Parkinson disease with the G2019S mutation in LRRK2 Neurology 2010 75 2017 2020 10.1212/WNL.0b013e3181ff9685 21115957 · DOI
  43. [45]Andres-Mateos E Unexpected lack of hypersensitivity in LRRK2 knock-out mice to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) J. Neurosci.: Off. J. Soc. Neurosci. 2009 29 15846 15850 10.1523/JNEUROSCI.4357-09.2009 PMC2846613 20016100 · DOI
  44. [46]Herzig MC LRRK2 protein levels are determined by kinase function and are crucial for kidney and lung homeostasis in mice Hum. Mol. Genet. 2011 20 4209 4223 10.1093/hmg/ddr348 21828077 PMC3188995 · DOI
  45. [47]Baptista MaS Loss of Leucine-Rich Repeat Kinase 2 (LRRK2) in rats leads to progressive abnormal phenotypes in peripheral organs PloS one 2013 8 e80705 10.1371/journal.pone.0080705 24244710 PMC3828242 · DOI
  46. [48]Herzig MC High LRRK2 levels fail to induce or exacerbate neuronal alpha-synucleinopathy in mouse brain PLoS One 2012 7 e36581 10.1371/journal.pone.0036581 22615783 PMC3352901 · DOI
  47. [50]Puccini JM Leucine-rich repeat kinase 2 modulates neuroinflammation and neurotoxicity in models of human immunodeficiency virus 1-associated neurocognitive disorders J. Neurosci. 2015 35 5271 5283 10.1523/JNEUROSCI.0650-14.2015 25834052 PMC4381000 · DOI
  48. [51]Härtlova A LRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages EMBO J. 2018 37 1 17 10.15252/embj.201798694 29789389 PMC6003659 · DOI
  49. [52]Boddu R Leucine-rich repeat kinase 2 deficiency is protective in rhabdomyolysis-induced kidney injury Hum. Mol. Genet. 2015 24 1 16 10.1093/hmg/ddv147 25904107 PMC4476452 · DOI
  50. [53]Derkinderen P LRRK2 expression in the enteric nervous system: ENSuring its significance Dig. Dis. Sci. 2017 62 826 827 10.1007/s10620-017-4500-7 28224253 · DOI
  51. [54]Yan J LRRK2 deficiency mitigates colitis progression by favoring resolution of inflammation and restoring homeostasis of gut microbiota Genomics 2022 114 110527 10.1016/j.ygeno.2022.110527 36455749 · DOI
  52. [55]Zhu Y Association between inflammatory bowel diseases and Parkinson’s disease: systematic review and meta-analysis Neural Regen. Res 2022 17 344 353 10.4103/1673-5374.317981 34269209 PMC8463981 · DOI
  53. [56]Bryce DK Characterization of the onset, progression, and reversibility of morphological changes in mouse lung after pharmacological inhibition of Leucine-rich kinase 2 kinase activity J. Pharm. Exp. Ther. 2021 377 11 19 10.1124/jpet.120.000217 33509901 · DOI
  54. [58]Wallings RL Tansey MG LRRK2 regulation of immune-pathways and inflammatory disease Biochem. Soc. Trans. 2019 47 1581 1595 10.1042/BST20180463 31769472 PMC6925522 · DOI
  55. [59]Rideout HJ The current state-of-the art of LRRK2-based biomarker assay development in Parkinson’s disease Front. Neurosci. 2020 14 4646 4656.e4 10.3389/fnins.2020.00865 PMC7461933 33013290 · DOI
  56. [60]Kay DM Kramer P Higgins D Zabetian CP Payami H Escaping Parkinson’s disease: a neurologically healthy octogenarian with the LRRK2 G2019S mutation Mov. Disord. 2005 20 1077 1078 10.1002/mds.20618 16001413 · DOI
  57. [61]Carmine Belin A Leucine-rich repeat kinase 2 (LRRK2) mutations in a Swedish Parkinson cohort and a healthy nonagenarian Mov. Disord. 2006 21 1731 1734 10.1002/mds.21016 16817197 · DOI
  58. [62]Marder, K. et al. Age-specific penetrance of LRRK2 G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium. Neurology85, 89–95 (2015). PMC4501942 26062626
  59. [63]Trinh J Molecular mechanisms defining penetrance of LRRK2-associated Parkinson’s disease Med. Genet. 2022 34 103 116 PMC11006382 38835904
  60. [64]Simpson C Prevalence of ten LRRK2 variants in Parkinson’s disease: a comprehensive review Parkinsonism Relat. Disord. 2022 98 103 113 10.1016/j.parkreldis.2022.05.012 35654702 · DOI
  61. [65]Lee AJ Penetrance estimate of LRRK2 p.G2019S mutation in individuals of non-Ashkenazi Jewish ancestry Mov. Disord. 2017 32 1432 1438 10.1002/mds.27059 28639421 PMC5656509 · DOI
  62. [66]Trinh J Guella I Farrer MJ Disease penetrance of late-onset parkinsonism: a meta-analysis JAMA Neurol. 2014 71 1535 1539 10.1001/jamaneurol.2014.1909 25330418 · DOI
  63. [67]Ruiz-Martínez J Penetrance in Parkinson’s disease related to the LRRK2 R1441G mutation in the Basque country (Spain) Mov. Disord. 2010 25 2340 2345 10.1002/mds.23278 20721916 · DOI
  64. [68]Vinagre-Aragón A A more homogeneous phenotype in Parkinson’s disease related to R1441G mutation in the LRRK2 Gene Front. Neurol. 2021 12 635396 10.3389/fneur.2021.635396 33763016 PMC7982912 · DOI
  65. [69]Crotty GF Association of caffeine and related analytes with resistance to Parkinson disease among LRRK2 mutation carriers: a metabolomic study Neurology 2020 95 e3428 e3437 10.1212/WNL.0000000000010863 32999056 PMC7836665 · DOI
  66. [70]MacLeod DA RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson’s disease risk Neuron 2013 77 425 439 10.1016/j.neuron.2012.11.033 23395371 PMC3646583 · DOI
  67. [71]Iwaki H Penetrance of Parkinson’s disease in LRRK2 p.G2019S carriers is modified by a polygenic risk score Mov. Disord. 2020 35 774 780 10.1002/mds.27974 31958187 PMC8975556 · DOI
  68. [72]Mirelman A Fall risk and gait in Parkinson’s disease: the role of the LRRK2 G2019S mutation Mov. Disord. 2013 28 1683 1690 10.1002/mds.25587 24123150 · DOI
  69. [73]Alcalay RN Parkinson disease phenotype in Ashkenazi Jews with and without LRRK2 G2019S mutations Mov. Disord. 2013 28 1966 1971 10.1002/mds.25647 24243757 PMC3859844 · DOI
  70. [74]Saunders-Pullman R Progression in the LRRK2-asssociated Parkinson disease population JAMA Neurol. 2018 75 312 319 10.1001/jamaneurol.2017.4019 29309488 PMC5885854 · DOI
  71. [75]Alcalay RN Neuropsychological performance in LRRK2 G2019S carriers with Parkinson’s disease Parkinsonism Relat. Disord. 2015 21 106 110 10.1016/j.parkreldis.2014.09.033 25434972 PMC4306614 · DOI
  72. [76]Saunders-Pullman R Association of olfactory performance with motor decline and age at onset in people with Parkinson disease and the LRRK2 G2019S variant Neurology 2022 99 e814 e823 10.1212/WNL.0000000000200737 35995594 PMC9484727 · DOI
  73. [77]Pont-Sunyer C Sleep disorders in Parkinsonian and nonparkinsonian LRRK2 mutation carriers PloS One 2015 10 e0132368 10.1371/journal.pone.0132368 26177462 PMC4503402 · DOI
  74. [78]Brockmann K Clinical and brain imaging characteristics in leucine-rich repeat kinase 2-associated PD and asymptomatic mutation carriers Mov. Disord. 2011 26 2335 2342 10.1002/mds.23991 21989859 · DOI
  75. [79]Thaler A Cerebral imaging markers of GBA and LRRK2 related Parkinson’s disease and their first-degree unaffected relatives Brain Topogr. 2018 31 1029 1036 10.1007/s10548-018-0653-8 29846835 · DOI
  76. [80]Simuni T Clinical and dopamine transporter imaging characteristics of Leucine Rich Repeat Kinase 2 (LRRK2) and Glucosylceramidase Beta (GBA) Parkinson’s disease participants in the Parkinson’s progression markers initiative: a cross-sectional study Mov. Disord. 2020 35 833 844 10.1002/mds.27989 32073681 PMC7231646 · DOI
  77. [81]Ahamadi M A disease progression model to quantify the nonmotor symptoms of Parkinson’s disease in participants with Leucine-rich repeat kinase 2 mutation Clin. Pharmacol. Ther. 2021 110 508 518 10.1002/cpt.2277 33894056 · DOI
  78. [82]Ahamadi M Development of a disease progression model for Leucine-rich repeat kinase 2 in Parkinson’s disease to inform clinical trial designs Clin. Pharmacol. Ther. 2020 107 553 562 10.1002/cpt.1634 31544231 PMC7939141 · DOI
  79. [83]Kozlovski T Hierarchical data-driven analysis of clinical symptoms among patients with Parkinson’s disease Front. Neurol. 2019 10 531 10.3389/fneur.2019.00531 31164863 PMC6536639 · DOI
  80. [84]Thaler A Survival rates among Parkinson’s disease patients who carry mutations in the LRRK2 and GBA genes Mov. Disord. 2018 33 1656 1660 10.1002/mds.27490 30288804 · DOI
  81. [85]Lanore A Differences in survival across monogenic forms of Parkinson’s disease Ann. Neurol. 2023 10.1002/ana.26636 36905164 · DOI
  82. [86]Zhang Y A meta-analysis of GBA-related clinical symptoms in Parkinson’s disease Parkinson’s Dis. 2018 2018 3136415 30363648 PMC6180987
  83. [87]Gan-Or Z Genotype-phenotype correlations between GBA mutations and Parkinson disease risk and onset Neurology 2008 70 2277 2283 10.1212/01.wnl.0000304039.11891.29 18434642 · DOI
  84. [88]Cilia R Survival and dementia in GBA-associated Parkinson’s disease: the mutation matters Ann. Neurol. 2016 80 662 673 10.1002/ana.24777 27632223 · DOI
  85. [89]Yahalom G Carriers of both GBA and LRRK2 mutations, compared to carriers of either, in Parkinson’s disease: risk estimates and genotype-phenotype correlations Parkinsonism Relat. Disord. 2019 62 179 184 10.1016/j.parkreldis.2018.12.014 30573413 · DOI
  86. [90]Omer N A possible modifying effect of the G2019S mutation in the LRRK2 gene on GBA Parkinson’s disease Mov. Disord. 2020 35 1249 1253 10.1002/mds.28066 32353202 · DOI
  87. [91]Ortega RA Association of dual LRRK2 G2019S and GBA variations with Parkinson disease progression JAMA Netw. open 2021 4 e215845 10.1001/jamanetworkopen.2021.5845 33881531 PMC8060834 · DOI
  88. [92]Wider C Dickson DW Wszolek ZK Leucine-rich repeat kinase 2 gene-associated disease: redefining genotype-phenotype correlation Neurodegener. Dis. 2010 7 175 179 10.1159/000289232 20197701 PMC2859237 · DOI
  89. [93]Kalia LV Clinical correlations with Lewy body pathology in LRRK2-related Parkinson disease JAMA Neurol. 2015 72 100 105 10.1001/jamaneurol.2014.2704 25401511 PMC4399368 · DOI
  90. [94]Garrido A synuclein RT-QuIC in cerebrospinal fluid of LRRK2-linked Parkinson’s disease Ann. Clin. Transl. Neurol. 2019 6 1024 1032 10.1002/acn3.772 31211166 PMC6562027 · DOI
  91. [95]Siderowf A Assessment of heterogeneity among participants in the Parkinson’s progression markers initiative cohort using α-synuclein seed amplification: a cross-sectional study Lancet Neurol. 2023 22 407 417 10.1016/S1474-4422(23)00109-6 37059509 PMC10627170 · DOI
  92. [96]Virreira Winter S Urinary proteome profiling for stratifying patients with familial Parkinson’s disease EMBO Mol. Med. 2021 29 4646 4656.e4 PMC7933820 33481347
  93. [97]Hadisurya, M. et al. Quantitative proteomics and phosphoproteomics of urinary extracellular vesicles define diagnostic and prognostic biosignatures for Parkinson’s Disease. medRxiv3, 64 (2022). PMC10172329 37165152
  94. [98]Lang AE Trial of cinpanemab in early Parkinson’s disease N. Engl. J. Med. 2022 387 408 420 10.1056/NEJMoa2203395 35921450 · DOI
  95. [99]Hasegawa K Familial parkinsonism: Study of original Sagamihara PARK8 (I2020T) kindred with variable clinicopathologic outcomes Parkinsonism Relat. Disord. 2009 15 300 306 10.1016/j.parkreldis.2008.07.010 18804399 PMC2702757 · DOI
  96. [100]Rajput A Parkinsonism, Lrrk2 G2019S, and tau neuropathology Neurology 2006 67 1506 1508 10.1212/01.wnl.0000240220.33950.0c 17060589 · DOI
  97. [101]Henderson MX Sengupta M Trojanowski JQ Lee VMY Alzheimer’s disease tau is a prominent pathology in LRRK2 Parkinson’s disease Acta Neuropathol. Commun. 2019 7 4646 4656.e4 10.1186/s40478-019-0836-x PMC6858668 31733655 · DOI
  98. [102]Chu Y Is Tau the initial pathology in dopaminergic nigrostriatal degeneration? Studies in Parkinsonism and Parkinson’s disease bioRxiv 2022 10.1101/2022.08.04.502831 · DOI
  99. [103]Brockmann K Association between CSF alpha-synuclein seeding activity and genetic status in Parkinson’s disease and dementia with Lewy bodies Acta Neuropathol. Commun. 2021 9 1 11 10.1186/s40478-021-01276-6 34717775 PMC8556894 · DOI
  100. [104]Park SA Jang YJ Kim MK Lee SM Moon SY Promising blood biomarkers for clinical use in Alzheimer’s disease: a focused update J. Clin. Neurol. (Korea) 2022 18 401 409 10.3988/jcn.2022.18.4.401 PMC9262460 35796265 · DOI
  101. [105]Daher JPL Leucine-rich Repeat Kinase 2 (LRRK2) pharmacological inhibition Abates α-Synuclein gene-induced neurodegeneration J. Biol. Chem. 2015 290 19433 19444 10.1074/jbc.M115.660001 26078453 PMC4528108 · DOI
  102. [106]Obergasteiger J Kinase inhibition of G2019S-LRRK2 enhances autolysosome formation and function to reduce endogenous alpha-synuclein intracellular inclusions Cell Death Discov. 2020 6 45 10.1038/s41420-020-0279-y 32550012 PMC7280235 · DOI
  103. [107]Deniston CK Structure of LRRK2 in Parkinson’s disease and model for microtubule interaction Nature 2020 588 344 349 10.1038/s41586-020-2673-2 32814344 PMC7726071 · DOI
  104. [108]Watanabe R The in situ structure of Parkinson’s disease-linked LRRK2 Biophys. J. 2020 118 486a 10.1016/j.bpj.2019.11.2690 PMC7869717 32783917 · DOI
  105. [109]Sejwal K Cryo-EM analysis of homodimeric full-length LRRK2 and LRRK1 protein complexes Sci. Rep. 2017 7 8667 10.1038/s41598-017-09126-z 28819229 PMC5561129 · DOI
  106. [110]Myasnikov, A. et al. Structural analysis of the full-length human LRRK2. Cell10.1016/j.cell.2021.05.004 (2021). PMC8887629 34107286
  107. [111]Guaitoli, G. et al. Structural model of the dimeric Parkinson’s protein LRRK2 reveals a compact architecture involving distant interdomain contacts. Proc. Natl Acad. Sci. USA10.1073/pnas.1523708113 (2016). PMC4968714 27357661
  108. [112]Vaikath NN Generation and characterization of novel conformation-specific monoclonal antibodies for α-synuclein pathology Neurobiol. Dis. 2015 10.1016/j.nbd.2015.04.009 25937088 · DOI
  109. [113]Kumar ST How specific are the conformation-specific α-synuclein antibodies? Characterization and validation of 16 α-synuclein conformation-specific antibodies using well-characterized preparations of α-synuclein monomers, fibrils and oligomers with distinct struct Neurobiol. Dis. 2020 146 105086 10.1016/j.nbd.2020.105086 32971232 · DOI
  110. [114]Takagawa T An increase in LRRK2 suppresses autophagy and enhances Dectin-1-induced immunity in a mouse model of colitis Sci. Transl. Med. 2018 10 eaan8162 10.1126/scitranslmed.aan8162 29875204 PMC6636639 · DOI · Paper page
  111. [115]Rocha EM LRRK2 inhibition prevents endolysosomal deficits seen in human Parkinson’s disease Neurobiol. Dis. 2020 134 104626 10.1016/j.nbd.2019.104626 31618685 PMC7345850 · DOI
  112. [116]Di Maio R LRRK2 activation in idiopathic Parkinson’s disease Sci. Transl. Med. 2018 10 eaar5429 10.1126/scitranslmed.aar5429 30045977 PMC6344941 · DOI
  113. [117]Wallings RL WHOPPA enables parallel assessment of Leucine-rich repeat kinase 2 and glucocerebrosidase enzymatic activity in Parkinson’s disease monocytes Front. Cell Neurosci. 2022 16 892899 10.3389/fncel.2022.892899 35755775 PMC9229349 · DOI
  114. [118]Fraser KB Ser(P)−1292 LRRK2 in urinary exosomes is elevated in idiopathic Parkinson’s disease Mov. Disord. 2016 31 1543 1550 10.1002/mds.26686 27297049 PMC5053851 · DOI
  115. [119]Fraser KB Moehle MS Alcalay RN West AB & LRRK2 Cohort Consortium. Urinary LRRK2 phosphorylation predicts parkinsonian phenotypes in G2019S LRRK2 carriers Neurology 2016 86 994 999 10.1212/WNL.0000000000002436 26865512 PMC4799717 · DOI
  116. [120]Taymans, J.-M. et al. Alterations in the LRRK2-Rab pathway in urinary extracellular vesicles as Parkinson’ s disease and pharmacodynamic biomarkers. npj Parkinsons Dis.9, 21 (2022). PMC9905493 36750568
  117. [122]Mabrouk OS Quantitative measurements of LRRK2 in human cerebrospinal fluid demonstrates increased levels in G2019S patients Front. Neurosci. 2020 14 4646 4656.e4 10.3389/fnins.2020.00526 PMC7262382 32523511 · DOI
  118. [123]Whiffin N The effect of LRRK2 loss-of-function variants in humans Nat. Med. 2020 26 869 877 10.1038/s41591-020-0893-5 32461697 PMC7303015 · DOI

Cited by

Sorted by citations

Authors
Taymans, J.-M., Fell, M., Greenamyre, T., Hirst, W. D., Mamais, A., Padmanabhan, S., Peter, I., Rideout, H., & Thaler, A.
Affiliations
  • Inserm (FR)
  • Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
  • University of Pittsburgh (US)
  • Biogen (United States) (US)
  • University of Florida (US)
  • Michael J. Fox Foundation (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • Biomedical Research Foundation of the Academy of Athens (GR)
  • Tel Aviv University (IL)
Corresponding author
Taymans, Jean-Marc
ORCID
Venue
npj Parkinson's Disease
Publisher
Springer Science and Business Media LLC
Published
2023-07-01
Volume
9
Issue
1
Pages
104-104
ISSN
2373-8057 (ISSN-L)
DOI
10.1038/s41531-023-00544-7
PMC
PMC10314919
OpenAlex
W4382798159
Cited by
153
References
5
Citations by year
2026: 50 · 2025: 60 · 2024: 37 · 2023: 6
FWCI
6.00
Type
journal article
Language
en
Open access
Licence
Locations
  • npj Parkinson s Disease (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Michael J. Fox Foundation for Parkinson’s Research (MJFF-022431)
  • U.S. Department of Health & Human Services | National Institutes of Health (1R21AG077269-01A1)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
LRRK2, Parkinson's disease, LRRK2 kinase, LRRK2 inhibitors, intestine, immune cells, disease progression biomarkers

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