Impact of 100 LRRK2 variants linked to Parkinson's disease on kinase activity and microtubule binding

Kalogeropulou, Alexia F.; Purlyte, Elena; Tonelli, Francesca; Lange, Sven M.; Wightman, Melanie; Prescott, Alan R.; Padmanabhan, Shalini; Sammler, Esther; Alessi, Dario R.

doi:10.1042/bcj20220161

Cited by 131Parkinson's Disease Mechanisms and TreatmentsProtein Kinase Regulation and GTPase SignalingNuclear Receptors and Signaling

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Impact of 100 LRRK2 variants linked to Parkinson's disease on kinase activity and microtubule binding

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Kalogeropulou, Alexia F., Purlyte, Elena, Tonelli, Francesca, Lange, Sven M., Wightman, Melanie, Prescott, Alan R., Padmanabhan, Shalini, Sammler, Esther, Alessi, Dario R.·2022·Biochemical Journal

DOI 10.1042/bcj20220161PMC PMC9472821

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Abstract

Mutations enhancing the kinase activity of leucine-rich repeat kinase-2 (LRRK2) cause Parkinson's disease (PD) and therapies that reduce LRRK2 kinase activity are being tested in clinical trials. Numerous rare variants of unknown clinical significance have been reported, but how the vast majority impact on LRRK2 function is unknown. Here, we investigate 100 LRRK2 variants linked to PD, including previously described pathogenic mutations. We identify 23 LRRK2 variants that robustly stimulate kinase activity, including variants within the N-terminal non-catalytic regions (ARM (E334K, A419V), ANK (R767H), LRR (R1067Q, R1325Q)), as well as variants predicted to destabilize the ROC:CORB interface (ROC (A1442P, V1447M), CORA (R1628P) CORB (S1761R, L1795F)) and COR:COR dimer interface (CORB (R1728H/L)). Most activating variants decrease LRRK2 biomarker site phosphorylation (pSer935/pSer955/pSer973), consistent with the notion that the active kinase conformation blocks their phosphorylation. We conclude that the impact of variants on kinase activity is best evaluated by deploying a cellular assay of LRRK2-dependent Rab10 substrate phosphorylation, compared with a biochemical kinase assay, as only a minority of activating variants (CORB (Y1699C, R1728H/L, S1761R) and kinase (G2019S, I2020T, T2031S)), enhance in vitro kinase activity of immunoprecipitated LRRK2. Twelve variants including several that activate LRRK2 and have been linked to PD, suppress microtubule association in the presence of a Type I kinase inhibitor (ARM (M712V), LRR (R1320S), ROC (A1442P, K1468E, S1508R), CORA (A1589S), CORB (Y1699C, R1728H/L) and WD40 (R2143M, S2350I, G2385R)). Our findings will stimulate work to better understand the mechanisms by which variants impact biology and provide rationale for variant carrier inclusion or exclusion in ongoing and future LRRK2 inhibitor clinical trials.

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Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology
Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., Grody, W. W., Hegde, M., Lyon, E., Spector, E., et al. (2015) · Genetics in Medicine · doi:10.1038/gim.2015.30 · Cited by 32,594
The mutational constraint spectrum quantified from variation in 141,456 humans
Karczewski, K. J., Francioli, L. C., Tiao, G., Cummings, B. B., Alföldi, J., Wang, Q., Collins, R. L., Laricchia, K. M., Ganna, A., Birnbaum, D. P., et al. (2020) · Nature · doi:10.1038/s41586-020-2308-7 · Cited by 9,434
THE GREEN FLUORESCENT PROTEIN
Tsien, R. Y. (1998) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.67.1.509 · Cited by 6,178
Untitled work
Yang (2021) · doi:10.1038/s41598-020-79139-8 · Cited by 5,035
ConSurf 2016: An improved methodology to estimate and visualize evolutionary conservation in macromolecules
Ashkenazy, H., Abadi, S., Martz, E., Chay, O., Mayrose, I., Pupko, T., & Ben-Tal, N. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw408 · Cited by 3,163
Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology
Zimprich, A. A., Biskup, S., Leitner, P., Lichtner, P., Farrer, M. J., Lincoln, S., Kachergus, J. M., Hulihan, M., Uitti, R. J., Calne, D. B., et al. (2004) · Neuron · doi:10.1016/j.neuron.2004.11.005 · Cited by 3,088
REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants
Ioannidis, N. M., Rothstein, J. H., Pejaver, V., Middha, S., McDonnell, S. K., Baheti, S., Musolf, A., Li, Q., Holzinger, E., Karyadi, D., et al. (2016) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2016.08.016 · Cited by 2,908
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Paisán‐Ruiz, C., Jain, S., Evans, E. W., Gilks, W. P., Simón, J., van der Brug, M., de Munaín, A. L., Aparicio, S. F., Gil, A. M., Khan, N. L., et al. (2004) · Neuron · doi:10.1016/j.neuron.2004.10.023 · Cited by 2,448
Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases
Steger, M., Tonelli, F., Ito, G., Davies, P., Trost, M., Vetter, M., Wachter, S., Lorentzen, E., Duddy, G., Wilson, S., et al. (2016) · eLife · doi:10.7554/elife.12813 · Cited by 1,042
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Ross, O. A., Soto‐Ortolaza, A. I., Heckman, M. G., Aasly, J. O., Abahuni, N., Annesi, G., Bacon, J. A., Bardien, S., Bozi, M., Brice, A., et al. (2011) · The Lancet Neurology · doi:10.1016/s1474-4422(11)70175-2 · Cited by 1,026
A common LRRK2 mutation in idiopathic Parkinson's disease
Gilks, W. P., Abou-Sleiman, P. M., Gandhi, S., Jain, S., Singleton, A., Lees, A. J., Shaw, K., Bhatia, K. P., Bonifati, V., Quinn, N. P., et al. (2005) · The Lancet · doi:10.1016/s0140-6736(05)17830-1 · Cited by 774
dbNSFP v2.0: A Database of Human Non-synonymous SNVs and Their Functional Predictions and Annotations
Liu, X., Jian, X., & Boerwinkle, E. (2013) · Human Mutation · doi:10.1002/humu.22376 · Cited by 595
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Di Fonzo, A., Rohé, C. F., Ferreira, J., Chien, H. F., Vacca, L., Stocchi, F., Guedes, L., Fabrizio, E., Manfredi, M., Vanacore, N., et al. (2005) · The Lancet · doi:10.1016/s0140-6736(05)17829-5 · Cited by 531
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Steger, M., Diez, F., Dhekne, H. S., Lis, P., Nirujogi, R. S., Karayel, O., Tonelli, F., Martinez, T. N., Lorentzen, E., Pfeffer, S. R., et al. (2017) · eLife · doi:10.7554/elife.31012 · Cited by 482
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Dzamko, N. L., Deák, M., Hentati, F., Reith, A. D., Prescott, A. R., Alessi, D. R., & Nichols, R. J. (2010) · Biochemical Journal · doi:10.1042/bj20100784 · Cited by 377
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Watanabe, R., Buschauer, R., Böhning, J., Audagnotto, M., Lasker, K., Lu, T., Boassa, D., Taylor, S. S., & Villa, E. (2020) · Cell · doi:10.1016/j.cell.2020.08.004 · Cited by 208
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Farrer, M. J., Stone, J. T., Lin, C., Dächsel, J. C., Hulihan, M., Haugarvoll, K., Ross, O. A., & Wu, R. (2007) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2006.12.001 · Cited by 205
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Kett, L. R., Boassa, D., Ho, C. C., Rideout, H. J., Hu, J., Terada, M., Ellisman, M. H., & Dauer, W. T. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr526 · Cited by 196
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Myasnikov, A. G., Zhu, H., Hixson, P. M., Xie, B., Yu, K., Pitre, A., Peng, J., & Sun, J. (2021) · Cell · doi:10.1016/j.cell.2021.05.004 · Cited by 193
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Doggett, E. A., Zhao, J., Mork, C. N., Hu, D., & Nichols, R. J. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07537.x · Cited by 95
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Self-citation
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Tasegian, A., Singh, F., Ganley, I. G., Reith, A. D., & Alessi, D. R. (2021) · Biochemical Journal · doi:10.1042/bcj20210375 · Cited by 79
Self-citation
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Schmidt, S. H., Knape, M. J., Boassa, D., Mumdey, N., Kornev, A. P., Ellisman, M. H., Taylor, S. S., & Herberg, F. W. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1900289116 · Cited by 77
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Schmidt, S. H., Weng, J., Aoto, P. C., Boassa, D., Mathea, S., Silletti, S., Torres-Paris, C., Hu, J., Wallbott, M., Komives, E. A., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2100844118 · Cited by 72
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Nixon‐Abell, J., Berwick, D. C., Grannò, S., Spain, V. A., Blackstone, C. D., & Harvey, K. (2016) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2016.00018 · Cited by 67
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McGrath, E., Waschbüsch, D., Baker, B. M., & Khan, A. R. (2019) · Small GTPases · doi:10.1080/21541248.2019.1666623 · Cited by 67
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Vides, E. G., Adhikari, A., Chiang, C. Y., Lis, P., Purlyte, E., Limouse, C., Shumate, J. L., Spínola-Lasso, E., Dhekne, H. S., Alessi, D. R., et al. (2022) · eLife · doi:10.7554/elife.79771 · Cited by 63
Self-citation
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Trabzuni, D., Ryten, M., Emmett, W., Ramasamy, A., Lackner, K. J., Zeller, T., WALKER, R. E., Smith, C., Lewis, P. A., Mamais, A., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0070724 · Cited by 50
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Weng, J., Aoto, P. C., Lorenz, R., Wu, J., Schmidt, S. H., Manschwetus, J. T., Sharma, P. K., Silletti, S., Mathea, S., Chatterjee, D., et al. (2022) · PLoS Biology · doi:10.1371/journal.pbio.3001427 · Cited by 25
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Taylor, S. S., Sharma, P. K., Weng, J., Aoto, P. C., Schmidt, S. H., Knapp, S., Mathea, S., & Herberg, F. W. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.538219 · Cited by 23
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Kim, J. J., Makarious, M. B., Bandrés‐Ciga, S., Gibbs, J. R., Ding, J., Hernandez, D. G., Brooks, J. A., Grenn, F. P., Iwaki, H., Singleton, A., et al. (2021) · Movement Disorders · doi:10.1002/mds.28488 · Cited by 21
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Zheng, Y., Liu, Y., Wu, Q., Hong, H., Zhou, H., Chen, J., Wang, H., Xian, W., Li, J., Liu, Z., et al. (2010) · European Journal of Neurology · doi:10.1111/j.1468-1331.2010.03164.x · Cited by 20
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Pillay, N. S., Ross, O. A., Christoffels, A. G., & Bardien, S. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.781816 · Cited by 9

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Westenberger, A., Skrahina, V., Usnich, T., Beetz, C., Vollstedt, E., Laabs, B., Paul, J. J., Curado, F., Skobalj, S., Gaber, H., et al. (2024) · Brain · doi:10.1093/brain/awae188 · Cited by 104
Uncovering the genetic basis of Parkinson's disease globally: from discoveries to the clinic
Lim, S., Tan, A. H., Ahmad‐Annuar, A., Okubadejo, N. U., Lohmann, K., Morris, H. R., Toh, T. S., Tay, Y. W., Lange, L. M., Bandrés‐Ciga, S., et al. (2024) · The Lancet Neurology · doi:10.1016/s1474-4422(24)00378-8 · Cited by 91
Self-citation
Leucine-Rich Repeat Kinases
Alessi, D. R., & Pfeffer, S. R. (2024) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-030122-051144 · Cited by 80
Self-citation
Parkinson’s Disease is Predominantly a Genetic Disease
Lim, S., & Klein, C. (2024) · Journal of Parkinson s Disease · doi:10.3233/jpd-230376 · Cited by 75
LRRK2 suppresses lysosome degradative activity in macrophages and microglia through MiT-TFE transcription factor inhibition
Yadavalli, N., & Ferguson, S. M. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2303789120 · Cited by 74
Systematic rare variant analyses identify RAB32 as a susceptibility gene for familial Parkinson’s disease
Hop, P. J., Lai, D., Keagle, P. J., Baron, D. M., Kenna, B., Kooyman, M., Shankaracharya, Halter, C. A., Straniero, L., Asselta, R., et al. (2024) · Nature Genetics · doi:10.1038/s41588-024-01787-7 · Cited by 70
A STING–CASM–GABARAP pathway activates LRRK2 at lysosomes
Bentley‐DeSousa, A., Roczniak-Ferguson, A., & Ferguson, S. M. (2024) · The Journal of Cell Biology · doi:10.1083/jcb.202310150 · Cited by 64
Inhibition of Parkinson’s disease–related LRRK2 by type I and type II kinase inhibitors: Activity and structures
Murillo, M. M. S., Suarez, A. C. V., Dederer, V., Chatterjee, D., Louro, J. A., Knapp, S., Mathea, S., & Leschziner, A. E. (2023) · Science Advances · doi:10.1126/sciadv.adk6191 · Cited by 59
Role of Autophagy Pathway in Parkinson’s Disease and Related Genetic Neurological Disorders
Themistokleous, C., Bagnoli, E., Parulekar, R., & Muqit, M. M. K. (2023) · Journal of Molecular Biology · doi:10.1016/j.jmb.2023.168144 · Cited by 51
Rab12 is a regulator of LRRK2 and its activation by damaged lysosomes
Wang, X., Bondar, V. V., Davis, O. B., Maloney, M. T., Agam, M. R., Chin, M. Y., Ho, A. C.-N., Ghosh, R., Leto, D. E., Joy, D. A., et al. (2023) · eLife · doi:10.7554/elife.87255 · Cited by 50
LRRK2 in Parkinson's disease: upstream regulation and therapeutic targeting
Xiong, Y., & Yu, J. (2024) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2024.07.003 · Cited by 48
Abundant non-inclusion α-synuclein pathology in Lewy body-negative LRRK2-mutant cases
Jensen, N. M., Vitic, Z., Antorini, M. R., Viftrup, T. B., Parkkinen, L., & Jensen, P. H. (2025) · Acta Neuropathologica · doi:10.1007/s00401-025-02871-w · Cited by 46
Updated MDSGene review on the clinical and genetic spectrum of LRRK2 variants in Parkinson´s disease
Krüger, C., Lim, S., Buhrmann, A., Fahrig, F. L., Gabbert, C., Bahr, N., Madoev, H., Marras, C., Klein, C., & Lohmann, K. (2025) · npj Parkinson s Disease · doi:10.1038/s41531-025-00881-9 · Cited by 45
Analysis of rare Parkinson’s disease variants in millions of people
Pitz, V., Makarious, M. B., Bandrés‐Ciga, S., Iwaki, H., Aslibekyan, S. W., Auton, A., Babalola, E., Bell, R. K., Bielenberg, J., Bryc, K., et al. (2024) · npj Parkinson s Disease · doi:10.1038/s41531-023-00608-8 · Cited by 44
Strategies for modeling aging and age-related diseases
Jothi, D., & Kulka, L. A. M. (2024) · npj Aging · doi:10.1038/s41514-024-00161-5 · Cited by 39
Genetics of Parkinson's Disease: From Causes to TreatmentPreprint
Westenberger, A., Brüggemann, N., & Klein, C. (2024) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a041774 · Cited by 39
Elevated urine BMP phospholipids in LRRK2 and VPS35 mutation carriers with and without Parkinson’s disease
Gomes, S., Garrido, A., Tonelli, F., Obiang, D., TOLOSA, E. S., Martı́, M. J., Ruiz‐Martínez, J., Vinagre‐Aragón, A., Hernández-Eguiazu, H., Croitoru, I. M., et al. (2023) · npj Parkinson s Disease · doi:10.1038/s41531-023-00482-4 · Cited by 37
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Regulatory imbalance between LRRK2 kinase, PPM1H phosphatase, and ARF6 GTPase disrupts the axonal transport of autophagosomes
Dou, D., Smith, E. M., Evans, C. S., Boecker, C. A., & Holzbaur, E. L. F. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112448 · Cited by 36
Autophagic stress activates distinct compensatory secretory pathways in neurons
Palumbos, S. D., Popolow, J., Goldsmith, J., & Holzbaur, E. L. F. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2421886122 · Cited by 33
Next-generation sequencing and bioinformatics in rare movement disorders
Zech, M., & Winkelmann, J. (2024) · Nature Reviews Neurology · doi:10.1038/s41582-023-00909-9 · Cited by 32
RAB3 phosphorylation by pathogenic LRRK2 impairs trafficking of synaptic vesicle precursors
Dou, D., Aiken, J., & Holzbaur, E. L. F. (2024) · Journal of Cell Biology · doi:10.1083/jcb.202307092 · Cited by 29
14-3-3 binding maintains the Parkinson’s associated kinase LRRK2 in an inactive state
Fiesco, J. A. M., Beilina, A. G., de la Cruz, A. A., Li, N., Metcalfe, R. D., Cookson, M., & Zhang, P. (2025) · Nature Communications · doi:10.1038/s41467-025-62337-1 · Cited by 27
LRRK2 phosphorylation status and kinase activity regulate (macro)autophagy in a Rab8a/Rab10-dependent manner
Kania, E., Long, J. S., McEwan, D. G., Welkenhuyzen, K., Rovere, R. L., Luyten, T., Halpin, J., Lobbestael, E., Baekelandt, V., Bultynck, G., et al. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-05964-0 · Cited by 26
The Role of LRRK2 in Intracellular Organelle Dynamics
Boecker, C. A. (2023) · Journal of Molecular Biology · doi:10.1016/j.jmb.2023.167998 · Cited by 24
RAB12-LRRK2 complex suppresses primary ciliogenesis and regulates centrosome homeostasis in astrocytes
Li, X., Zhu, H., Huang, B. T., Li, X., Kim, H., Tan, H., Zhang, Y., Choi, I., Peng, J., Xu, P., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-52723-6 · Cited by 23
The emerging role of LRRK2 in tauopathies
Herbst, S., Lewis, P. A., & Morris, H. R. (2022) · Clinical Science · doi:10.1042/cs20220067 · Cited by 23
Overview of the Impact of Pathogenic LRRK2 Mutations in Parkinson’s Disease
Ito, G., & Utsunomiya‐Tate, N. (2023) · Biomolecules · doi:10.3390/biom13050845 · Cited by 23
Patterns of TDP ‐43 Deposition in Brains with LRRK2 G2019S Mutations
Agin‐Liebes, J., Hickman, R. A., Vonsattel, J. P., Faust, P. L., Flowers, X. E., Utkina-Sosunova, I. V., Ntiri, J., Mayeux, R. P., Surface, M., Marder, K. S., et al. (2023) · Movement Disorders · doi:10.1002/mds.29449 · Cited by 23
The landscape of rare genetic variation associated with inflammatory bowel disease and Parkinson’s disease comorbidity
Kars, M. E., Wu, Y., Stenson, P. D., Cooper, D. N., Burisch, J. M., Peter, I., & Itan, Y. (2024) · Genome Medicine · doi:10.1186/s13073-024-01335-2 · Cited by 23
Exome sequencing in Asian populations identifies low-frequency and rare coding variation influencing Parkinson’s disease risk
Chew, E. G. Y., Liu, Z., Li, Z., Chung, S. J., Lian, M. M., Tandiono, M., Heng, Y. J., Ng, E., Tan, L. C. S., Chng, W. L., et al. (2024) · Nature Aging · doi:10.1038/s43587-024-00760-7 · Cited by 23
Endogenous LRRK2 and PINK1 function in a convergent neuroprotective ciliogenesis pathway in the brain
Bagnoli, E., Lin, Y., Burel, S., Jaimon, E., Antico, O., Themistokleous, C., Nikoloff, J. M., Squires, S., Morella, I., Watzlawik, J. O., et al. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2412029122 · Cited by 21
Self-citation
Parkinson's disease genetics across diverse ancestries: an observational genetic study of causal and risk variants with translational implications
Lange, L. M., Fang, Z., Makarious, M. B., Kuznetsov, N., Brolin, K. A., Ballard, S., Bardien, S., Doquenia, M. L. M., Heutink, P., Houlden, H., et al. (2026) · The Lancet Neurology · doi:10.1016/s1474-4422(26)00198-5 · Cited by 21
Membrane remodeling properties of the Parkinson’s disease protein LRRK2
Wang, X., Espadas, J., Wu, Y., Cai, S., Ge, J., Shao, L., Roux, A., & Camilli, P. V. D. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2309698120 · Cited by 20
How Parkinson’s Disease-Linked LRRK2 Mutations Affect Different CNS Cell Types
Bailey, H. M., & Cookson, M. (2024) · Journal of Parkinson s Disease · doi:10.3233/jpd-230432 · Cited by 18
Capturing the domain crosstalk in full length LRRK2 and LRRK2RCKW
Störmer, E., Weng, J., Wu, J., Bertinetti, D., Sharma, P. K., Ma, W., Herberg, F. W., & Taylor, S. S. (2023) · Biochemical Journal · doi:10.1042/bcj20230126 · Cited by 17
An Update on the Interplay between LRRK2, Rab GTPases and Parkinson’s Disease
Komori, T., & Kuwahara, T. (2023) · Biomolecules · doi:10.3390/biom13111645 · Cited by 16
A designed ankyrin-repeat protein that targets Parkinson’s disease-associated LRRK2
Dederer, V., Murillo, M. M. S., Karasmanis, E. P., Hatch, K. S., Chatterjee, D., Preuß, F., Azeez, K. R. A., Nguyen, L. V., Galicia, C., Dreier, B., et al. (2024) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2024.107469 · Cited by 15
Structural biology of Parkinson’s disease-associated leucine-rich repeat kinase 2 (LRRK2)
Leschziner, A. E. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.110376 · Cited by 14
Selective dopaminergic neurotoxicity modulated by inherent cell-type specific neurobiology
Currim, F., Tanwar, R., Brown-Leung, J. M., Paranjape, N., Liu, J., Sanders, L. H., Doorn, J. A., & Cannon, J. R. (2024) · NeuroToxicology · doi:10.1016/j.neuro.2024.06.016 · Cited by 14
Role of LRRK2 in axonal transport and Parkinson’s disease
Twellsieck, B., & Boecker, C. A. (2025) · Biochemical Journal · doi:10.1042/bcj20253133 · Cited by 13
Team Science Approaches to Unravel Monogenic Parkinson's Disease on a Global Scale
Junker, J., Lange, L. M., Vollstedt, E., Roopnarain, K., Doquenia, M. L. M., Ahmad‐Annuar, A., Avenali, M., Bardien, S., Bahr, N., Ellis, M., et al. (2024) · Movement Disorders · doi:10.1002/mds.29925 · Cited by 13
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The New p. F1700L LRRK2 Variant Causes Parkinson's Disease by Extensively Increasing Kinase Activity
Borsche, M., Pratuseviciute, N., Schaake, S., Hinrichs, F., Morel, G., Uter, J. C., Lohmann, K., Klein, C., Alessi, D. R., Hagenah, J. M., et al. (2023) · Movement Disorders · doi:10.1002/mds.29385 · Cited by 12
Self-citation
Clinical and functional evidence for the pathogenicity of the LRRK2 p.Arg1067Gln variant
Lim, S., Toh, T. S., Hor, J. W., Lim, J. L., Lit, L. C., Ahmad‐Annuar, A., Tay, Y. W., Foo, J. N., Ng, E. Y., Muthusamy, K. A., et al. (2025) · npj Parkinson s Disease · doi:10.1038/s41531-025-00884-6 · Cited by 11
Self-citation
Development of mutation-selective LRRK2 kinase inhibitors as precision medicine for Parkinson's disease and other diseases for which carriers are at increased risk
Leśniak, R. K., Nichols, R. J., & Montine, T. J. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2022.1016040 · Cited by 11
LRRK2 exonic variants are associated with lysosomal hydrolase activities and lysosphingolipid alterations in Parkinson's disease
Usenko, T. S., Senkevich, K. A., Basharova, K. S., Bezrukova, A. I., Baydakova, G., Tyurin, A., Beletskaia, M., Kulabukhova, D. G., Grunina, M. N., Emelyanov, A., et al. (2023) · Gene · doi:10.1016/j.gene.2023.147639 · Cited by 11
Leucine-Rich Repeat Kinase 2: Pathways to Parkinson's DiseasePreprint
Pfeffer, S. R., & Alessi, D. R. (2025) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a041620 · Cited by 10
Self-citation
Intramolecular feedback regulation of the LRRK2 Roc G domain by a LRRK2 kinase-dependent mechanism
Gilsbach, B. K., Ho, F. Y., Riebenbauer, B., Zhang, X., Guaitoli, G., Kortholt, A., & Gloeckner, C. J. (2024) · eLife · doi:10.1101/2023.07.31.549909 · Cited by 9
iSCORE-PD: an isogenic stem cell collection to research Parkinson’s disease
Busquets, O., Li, H., Syed, K. M., Jerez, P. Á., Dunnack, J., Bu, R. L., Verma, Y., Pangilinan, G. R., Martin, A., Straub, J., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-74355-8 · Cited by 9
LRRK2 ‐Targeting Therapies March Through the Valley of Death
West, A. B., & Schwarzschild, M. A. (2023) · Movement Disorders · doi:10.1002/mds.29343 · Cited by 9
Structure and regulation of full-length human leucine-rich repeat kinase 1
Metcalfe, R. D., Martinez Fiesco, J. A., Bonet-Ponce, L., Kluss, J. H., Cookson, M. R., & Zhang, P. (2023) · Nature Communications · doi:10.1038/s41467-023-40532-2 · Cited by 8
Large-scale copy number variant analysis in genes linked to Parkinson´s disease
Landoulsi, Z., Lohmann, K., Vollstedt, E., Wedgwood-Benn, E., Niestroj, L., Laabs, B., Sendel, S., Balck, A., Borsche, M., Lal, D., et al. (2025) · npj Parkinson s Disease · doi:10.1038/s41531-025-01076-y · Cited by 8
Clinical characteristics and pathophysiological properties of newly discovered LRRK2 variants associated with Parkinson's disease
Tezuka, T., Ishiguro, M., Taniguchi, D., Osogaguchi, E., Shiba‐Fukushima, K., Ogata, J., Ishii, R., Ikeda, A., Li, Y., Yoshino, H., et al. (2024) · Neurobiology of Disease · doi:10.1016/j.nbd.2024.106571 · Cited by 8
The design and development of LRRK2 inhibitors as novel therapeutics for Parkinson’s disease
Bai, X., Zhu, J., Chen, Y., & Sun, H. (2024) · Future Medicinal Chemistry · doi:10.1080/17568919.2024.2444875 · Cited by 8
Comprehensive genetic screening of early-onset dementia patients in an Austrian cohort-suggesting new disease-contributing genes
Silvaieh, S., König, T., Wurm, R., Parvizi, T., Berger–Sieczkowski, E., Goeschl, S., Hotzy, C., Wagner, M., Berutti, R., Sammler, E. M., et al. (2023) · Human Genomics · doi:10.1186/s40246-023-00499-z · Cited by 8
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Roles of LRRK2 and its orthologs in protecting against neurodegeneration and neurodevelopmental defects
Nguyen, A. P. T., Nguyen, L. T. N., Stokke, B. A., & Quinn, C. C. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1569733 · Cited by 7
Exploring the Impact of LRRK2 WD40 G2294R Mutation on Conformation and Dimerisation Dynamics: Insights From Molecular Dynamics Simulation
Wei, C., Heh, C. H., & Chin, S. P. (2025) · Journal of Cellular Biochemistry · doi:10.1002/jcb.70011 · Cited by 7
Inflammation and IL-4 regulate Parkinson’s and Crohn’s disease associated kinase LRRK2
Dikovskaya, D., Pemberton, R., Taylor, M., Tasegian, A., Bhattacharya, P., Zeneviciute, K., Sammler, E. M., Howden, A. J. M., Alessi, D. R., & Swamy, M. (2025) · EMBO Reports · doi:10.1038/s44319-025-00473-x · Cited by 7
Self-citation
Leucine-rich repeat kinase 2 biomarkers for Parkinson’s disease
Dzamko, N. L. (2025) · Biochemical Journal · doi:10.1042/bcj20253099 · Cited by 6
Pathological Protein Targets in Parkinson’s Disease: Progress Towards the Development of Disease-Modifying Therapies
Dzamko, N. L. (2026) · CNS Drugs · doi:10.1007/s40263-026-01275-y · Cited by 6
Low-dose radiation decreases Lrrk2 levels in the striatum of large mammalian brains: New venues to treat Parkinson's disease?
Iacono, D., Murphy, E. K., Stimpson, C. D., Perl, D. P., & Day, R. M. (2024) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2024.107024 · Cited by 6
PPM1M, an LRRK2-counteracting, phosphoRab12-preferring phosphatase with a potential link to Parkinson’s disease
Chiang, C. Y., Pratuseviciute, N., Lin, Y., Adhikari, A., Yeshaw, W. M., Flitton, C., Sherpa, P., Tonelli, F., Rektorová, I., Lynch, T., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116031 · Cited by 6
Self-citation
Ex Vivo LRRK2 Activation in Asian G2385R and R1628P Variant Carriers and Idiopathic Parkinson's Disease
Toh, T. S., Lit, L. C., Lim, S., Hor, J. W., Lew, C. Y., Anuar, A. N. K., Tay, Y. W., Black, K., Lim, J. L., Zulkefli, J., et al. (2026) · Movement Disorders · doi:10.1002/mds.70314 · Cited by 6
Self-citation
Catalyzing a Cure: Discovery and development of LRRK2 inhibitors for the treatment of Parkinson’s disease
Baidya, A. T. K., Deshwal, S., Das, B., Mathew, A. T., Devi, B., Sandhir, R., & Kumar, R. (2023) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2023.106972 · Cited by 6
The LRRK2 p.L1795F variant causes Parkinson’s disease in the European population
Lange, L. M., Levine, K. S., Fox, S. H., Marras, C., Ahmed, N., Kuznetsov, N., Vitale, D., Iwaki, H., Lohmann, K., Marsili, L., et al. (2025) · npj Parkinson s Disease · doi:10.1038/s41531-025-00896-2 · Cited by 5
Dissecting the effects of GTPase and kinase domain mutations on LRRK2 endosomal localization and activity
Rinaldi, C., Waters, C. S., Li, Z., Kumbier, K., Rao, L., Nichols, R. J., Jacobson, M. P., Wu, L. F., & Altschuler, S. J. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112447 · Cited by 5
Functional and Structural Characterization of LRRK2 p. V1447L in Parkinson's Disease
Pratuseviciute, N., Lis, P., Weber, S., Gruchy, N., Arnaud, L., Alessi, D. R., & Sammler, E. M. (2025) · Movement Disorders · doi:10.1002/mds.30284 · Cited by 4
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Membrane Dysfunction as a Central Mechanism in LRRK2-Associated Parkinson’s Disease: Comparative Analysis of G2019S and I1371V Variants
Singh, K., Banerjee, R., Potdar, C., Shaw, A., Rakshith, R., Kamble, N. L., Holla, V., Yadav, R., Pal, P. K., & Datta, I. (2026) · Cells · doi:10.3390/cells15040342 · Cited by 4
Targeting of kinases to treat neurodegenerative diseases
Shomali, T., & Trempe, J.-F. (2026) · Pharmacological Reviews · doi:10.1016/j.pharmr.2026.100128 · Cited by 4
The structural basis for LRRK2’s activation and autoinhibition
Suarez, A. C. V., Hatch, K. S., Bodrug, T., Gai, W., Surridge, K. J., Moussikhina, E., Nguyen, K. H. V., Murillo, M. M. S., Callahan, R., Xiong, E., et al. (2026) · Cell · doi:10.1016/j.cell.2026.07.027 · Cited by 4
A new LRRK2 variant in a family with Parkinson’s disease affects binding to RAB8A
Vela, L., Pascual, A., Montal, V., Guerrero, C., Lopez, M. O., Guallar, V., Palau, F., & Hoenicka, J. (2025) · npj Parkinson s Disease · doi:10.1038/s41531-025-00989-y · Cited by 4
Prevalence and Clinical Characteristics of the LRRK2 p. L1795F Variant in Central Europeans with Early‐Onset and Familial Parkinson's Disease
Ostrožovičová, M., Tamás, G., Atputhavadivel, A., Dušek, P., Grofik, M., Haň, V., Hollý, P., Jech, R., Kalinová, K., Klivènyi, P., et al. (2025) · Movement Disorders Clinical Practice · doi:10.1002/mdc3.70045 · Cited by 4
Research in movement disorders in 2022: a new era of biomarker and treatment development
Klein, C., & Bloem, B. R. (2022) · The Lancet Neurology · doi:10.1016/s1474-4422(22)00494-x · Cited by 4
15-Lipoxygenase-Mediated Lipid Peroxidation Regulates LRRK2 Kinase ActivityPreprint
Keeney, M. T., Hoffman, E. K., Weir, J., Wagner, W. G., Rocha, E. M., Castro, S. L., Farmer, K., Fazzari, M., Maio, R. D., Konradi, A. W., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.06.12.598654 · Cited by 4
Cryo-electron tomography reveals the microtubule-bound form of inactive LRRK2
Chen, S., Basiashvili, T., Hutchings, J., Sanz Murillo, M., Villagran Suarez, A., Xiong, E., Alegrio Louro, J., Leschziner, A. E., & Villa, E. (2025) · eLife · doi:10.7554/elife.100799.3 · Cited by 3
Proximity proteomics reveals a co-evolved LRRK2-regulatory network linked to centrosomes
Eckert, M., Miglionico, P., Izzi, F., Rosa, N. D. O., Riebenbauer, B., Ueffing, M., Raimondi, F., & Gloeckner, C. J. (2026) · EMBO Reports · doi:10.1038/s44319-026-00806-4 · Cited by 3
LRRK2 rare-variant per-domain genetic burden in Parkinson’s Disease: association confined to the kinase domain
Parlar, S. C., Senkevich, K. A., Yu, E., Ruskey, J. A., Ahmad, J., Asayesh, F., Spiegelman, D., Waters, C., Monchi, O., Dauvilliers, Y. A., et al. (2025) · npj Parkinson s Disease · doi:10.1038/s41531-025-00934-z · Cited by 3
LRRK2 kinase mediates increased GCase activity in microglia in response to IFNγ-induced proinflammatory stimulation
MacDougall, E. J., Chen, C. X. ‐., Deneault, É., You, Z., Kalaydjian, D., Abdian, N., Durcan, T. M., Senkevich, K. A., Gan‐Or, Z., & Fon, E. A. (2026) · npj Parkinson s Disease · doi:10.1038/s41531-026-01310-1 · Cited by 3
Addressing the Challenges of Translating LRRK2 Biology into Disease‐Modifying Therapies: The LRRK2 Investigative Therapeutics Exchange Initiative
Sammler, E. M., Tonelli, F., Durborow, M., McNasby, J., Sherer, T., Ahmed, M., Djurić, S. W., Merchant, K., Reith, A., Schoepp, D. D., et al. (2026) · Movement Disorders · doi:10.1002/mds.70397 · Cited by 3
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Multi-cohort, cross-species urinary proteomics reveals signatures of LRRK2 dysfunction in Parkinson’s disease
Vu, D. T., Sibran, W., Metousis, A., Vandewynckel, L., Eraslan, B., Goveas, L. M., Itang, E. C. M., Deldycke, C., Garcia, A. F., Lefebvre, R., et al. (2026) · Molecular Systems Biology · doi:10.1038/s44320-026-00190-0 · Cited by 3
Intramolecular feedback regulation of the LRRK2 Roc G domain by a LRRK2 kinase-dependent mechanismPreprint
Gilsbach, B. K., Ho, F. Y., Riebenbauer, B., Zhang, X., Guaitoli, G., Kortholt, A., & Gloeckner, C. J. (2023) · eLife · doi:10.7554/elife.91083 · Cited by 3
The LRRK2 P1446L mutation triggers dopaminergic neurodegeneration via DAPK1-mediated microglial neuroinflammation and neuronal apoptosis
Ding, L., Shu, H., Chen, M., Liang, F., Gan, T., Huang, X., Liang, X., Luo, K., Qiu, L., Huang, W., et al. (2025) · npj Parkinson s Disease · doi:10.1038/s41531-025-01234-2 · Cited by 2
The genetic spectrum of LRRK2 variants in Parkinson’s disease: findings from a large Chinese cohort
Wan, J., Pan, H., Chang, D., Zhao, Y., Xu, Q., Yao, L., Sun, Q., 张学伟, He, R., Wang, C., et al. (2026) · npj Parkinson s Disease · doi:10.1038/s41531-026-01315-w · Cited by 2
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Ali, H., Mondal, B., Pinto, A., Sarkar, C., Panda, B. K., Rupanagudi, K. V., Holla, V. V., Nagaraj, T., Bhat, S. G., Prasad, S., et al. (2026) · npj Parkinson s Disease · doi:10.1038/s41531-026-01462-0 · Cited by 1
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eLife Assessment: Structural insights in the GTP-driven monomerization and activation of a bacterial LRRK2 homologue using allosteric nanobodies
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Tezuka, T., Ishiguro, M., Taniguchi, D., Osogaguchi, E., Shiba‐Fukushima, K., Ogata, J., Ishii, R., Ikeda, A., Li, Y., Yoshino, H., et al. (2024) · Neurobiology of Disease · doi:10.1016/j.nbd.2024.106571 · Cited by 8
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Wang, X., Negrou, E., Maloney, M. T., Bondar, V. V., Andrews, S. V., Montalban, M., Llapashtica, C., Maciuca, R. D., Nguyen, H. N., Solanoy, H. O., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-91943-4 · Cited by 50

Authors: Kalogeropulou, A. F., Purlyte, E., Tonelli, F., Lange, S. M., Wightman, M., Prescott, A. R., Padmanabhan, S., Sammler, E., & Alessi, D. R.
Affiliations: University of Dundee (GB)
Michael J. Fox Foundation (US)
Corresponding author: Alessi, Dario R.
ORCID: Kalogeropulou, Alexia F.
Purlyte, Elena
Tonelli, Francesca
Lange, Sven M.
Prescott, Alan R.
Padmanabhan, Shalini
Sammler, Esther
Alessi, Dario R.
Venue: Biochemical Journal
Publisher: Portland Press Ltd.
Published: 2022-09-06
Volume: 479
Issue: 17
Pages: 1759-1783
ISSN: 0264-6021 (ISSN-L)
1470-8728
DOI: 10.1042/bcj20220161
PMC: PMC9472821
OpenAlex: W4290803974
Cited by: 129
References: 71
Citations by year: 2026: 32 · 2025: 33 · 2024: 35 · 2023: 25 · 2022: 4
FWCI: 12.89
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Biochemical Journal (publishedVersion, cc-by)
bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Discovery Research Portal (University of Dundee) (acceptedVersion, cc-by)
Funders: Michael J. Fox Foundation for Parkinson's Research (ASAP‐000463)
GlaxoSmithKline
Merck KGaA
Parkinson's UK (H-1701)
Medical Research Council (MC_UU_00018/1)
Topics: Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
Keywords: LRRK2, Parkinson's disease, kinase activity, microtubule binding, variants of uncertain significance, kinase activation, Rab10 phosphorylation, LRRK2 inhibitors, protein stability, rare variants
MeSH terms: Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Humans, Microtubules, Mutation, Parkinson Disease, Phosphorylation, Protein Binding

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Impact of 100 LRRK2 variants linked to Parkinson's disease on kinase activity and microtubule binding

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