LRRK2 kinase inhibition prevents pathological microglial phagocytosis in response to HIV-1 Tat protein
Open accessAbstract
BACKGROUND: Human Immunodeficiency Virus-1 (HIV-1) associated neurocognitive disorders (HANDs) are accompanied by significant morbidity, which persists despite the use of combined antiretroviral therapy (cART). While activated microglia play a role in pathogenesis, changes in their immune effector functions, including phagocytosis and proinflammatory signaling pathways, are not well understood. We have identified leucine-rich repeat kinase 2 (LRRK2) as a novel regulator of microglial phagocytosis and activation in an in vitro model of HANDs, and hypothesize that LRRK2 kinase inhibition will attenuate microglial activation during HANDs. METHODS: We treated BV-2 immortalized mouse microglia cells with the HIV-1 trans activator of transcription (Tat) protein in the absence or presence of LRRK2 kinase inhibitor (LRRK2i). We used Western blot, qRT-PCR, immunocytochemistry and latex bead engulfment assays to analyze LRRK2 protein levels, proinflammatory cytokine and phagocytosis receptor expression, LRRK2 cellular distribution and phagocytosis, respectively. Finally, we utilized ex vivo microfluidic chambers containing primary hippocampal neurons and BV-2 microglia cells to investigate microglial phagocytosis of neuronal axons. RESULTS: We found that Tat-treatment of BV-2 cells induced kinase activity associated phosphorylation of serine 935 on LRRK2 and caused the formation of cytoplasmic LRRK2 inclusions. LRRK2i decreased Tat-induced phosphorylation of serine 935 on LRRK2 and inhibited the formation of Tat-induced cytoplasmic LRRK2 inclusions. LRRK2i also decreased Tat-induced process extension in BV-2 cells. Furthermore, LRRK2i attenuated Tat-induced cytokine expression and latex bead engulfment. We examined relevant cellular targets in microfluidic chambers and found that Tat-treated BV-2 microglia cells cleared axonal arbor and engulfed neuronal elements, whereas saline treated controls did not. LRRK2i was found to protect axons in the presence of Tat-activated microglia, as well as AnnexinV, a phosphatidylserine-binding protein. In addition, LRRK2i decreased brain-specific angiogenesis inhibitor 1 (BAI1) receptor expression on BV-2 cells after Tat-treatment, a key receptor in phosphatidylserine-mediated phagocytosis. CONCLUSION: Taken together, these results implicate LRRK2 as a key player in microglial inflammation and, in particular, in the phagocytosis of neuronal elements. These studies show that LRRK2 kinase inhibition may prove an effective therapeutic strategy for HANDs, as well as other neuroinflammatory conditions.
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Extracellular α-synuclein aggregates can interact with microglia via TLR2 to activate the LRRK2-NFATc2 pathway and produce a pro-inflammatory phenotype, and can also interact with other receptors to initiate LRRK2-dependent aggregate phagocytosis and clearance via lysosomal pathways.
“Extracellular α-synuclein aggregates may interact with microglia in at least two different ways: on one hand, they may stimulate TLR2 to activate the LRRK2-NFATc2 pathway and produce a pro-inflammatory phenotype, as shown in the present study; on the other, they can also interact with other receptors to initiate LRRK2-dependent aggregate phagocytosis (48) and clearance via lysosomal pathways (49,”
From LRRK2 mediates microglial neurotoxicity via NFATc2 in rodent models of synucleinopathies (2020) · cites this paper as [48]
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Cites
NIH Image to ImageJ: 25 years of image analysis
Schneider, C. A., Rasband, W. S., & Eliceiri, K. W. (2012) · Nature Methods · doi:10.1038/nmeth.2089 · Cited by 64,638 · see citing works
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 3,024 · see citing works
Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease
the NIDDK IBD Genetics Consortium, Barrett, J. C., the Belgian-French IBD Consortium, the Wellcome Trust Case Control Consortium, Hansoul, S., Nicolae, D. L., Cho, J. H., Duerr, R. H., Rioux, J. D., Brant, S. R., et al. (2008) · Nature Genetics · doi:10.1038/ng.175 · Cited by 2,593 · see citing works
Heaton, R. K., Clifford, D. B., Franklin, D. R., Woods, S. P., Ake, C., Vaida, F., Ellis, R. J., Letendre, S. L., Marcotte, T. D., Atkinson, J. H., et al. (2010) · Neurology · doi:10.1212/wnl.0b013e318200d727 · Cited by 2,353 · see citing works
Computer Control of Microscopes Using µManager
Edelstein, A., Amodaj, N., Hoover, K., Vale, R. D., & Stuurman, N. (2010) · Current Protocols in Molecular Biology · doi:10.1002/0471142727.mb1420s92 · Cited by 1,678 · see citing works
Design and validation of a tool for neurite tracing and analysis in fluorescence microscopy images
Meijering, E. H. W., Jacob, M., Sarria, J. ‐. F., Steiner, P., Hirling, H., & Unser, M. A. (2004) · Cytometry Part A · doi:10.1002/cyto.a.20022 · Cited by 1,611 · see citing works
Genomewide Association Study of Leprosy
Zhang, F., Huang, W., Chen, S., Sun, L., Liu, H. D., Li, Y., Cui, Y., Yan, X., Yang, H., Yang, R., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0903753 · Cited by 1,037 · see citing works
Kim, W., Mohney, R. P., Wilson, B. C., Jeohn, G., Liu, B., & Hong, J. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-16-06309.2000 · Cited by 881 · see citing works
BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module
Park, D., Tosello‐Trampont, A., Elliott, M. R., Lu, M., Haney, L. B., Ma, Z., Klibanov, A. L., Mandell, J. W., & Ravichandran, K. S. (2007) · Nature · doi:10.1038/nature06329 · Cited by 848 · see citing works
Cytokine expression in the brain during the acquired immunodeficiency syndrome
Tyor, W. R., Glass, J. D., Griffin, J. W., Becker, P. S., McArthur, J. C., Bezman, L., & Griffin, D. E. (1992) · Annals of Neurology · doi:10.1002/ana.410310402 · Cited by 566 · see citing works
The Familial Parkinsonism Gene LRRK2 Regulates Neurite Process Morphology
MacLeod, D., Dowman, J., Hammond, R., Leete, T., Inoue, K., & Abeliovich, A. (2006) · Neuron · doi:10.1016/j.neuron.2006.10.008 · Cited by 561 · see citing works
Localization of LRRK2 to membranous and vesicular structures in mammalian brain
Biskup, S., Moore, D. J., Celsi, F., Higashi, S., West, A. B., Andrabi, S. A., Kurkinen, K. M. A., Yu, S., Savitt, J. M., Waldvogel, H. J., et al. (2006) · Annals of Neurology · doi:10.1002/ana.21019 · Cited by 511 · see citing works
Tong, Y., Yamaguchi, H., Giaime, E., Boyle, S., Kopan, R., Kelleher, R. J., & Shen, J. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1004676107 · Cited by 502 · see citing works
Role of autophagy in G2019S‐LRRK2‐associated neurite shortening in differentiated SH‐SY5Y cells
Plowey, E. D., Cherra, S. J., Liu, Y., & Chu, C. T. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05217.x · Cited by 493 · see citing works
Masliah, E., Ellis, R. J., Mallory, M. E., Heaton, R. K., Marcotte, T. D., Nelson, J. A. E., Grant, I., Atkinson, J. H., Wiley, C. A., Achim, C. L., et al. (1997) · Annals of Neurology · doi:10.1002/ana.410420618 · Cited by 475 · see citing works
Microfluidic culture platform for neuroscience research
Park, J. W., Vahidi, B., Taylor, A. M., Rhee, S. W., & Jeon, N. L. (2006) · Nature Protocols · doi:10.1038/nprot.2006.316 · Cited by 466 · see citing works
LRRK2 Inhibition Attenuates Microglial Inflammatory Responses
Moehle, M. S., Webber, P. J., Tse, T., Sukar, N., Standaert, D. G., DeSilva, T. M., Cowell, R. M., & West, A. B. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.5601-11.2012 · Cited by 463 · see citing works
Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2
Deng, X., Dzamko, N. L., Prescott, A. R., Davies, P., Liu, Q., Yang, Q., Lee, J., Patricelli, M. P., Nomanbhoy, T. K., Alessi, D. R., et al. (2011) · Nature Chemical Biology · doi:10.1038/nchembio.538 · Cited by 424 · see citing works
LRRK2 Is Involved in the IFN-γ Response and Host Response to Pathogens
Gardet, A., Benita, Y., Li, C., Sands, B. E., Ballester, I., Stevens, C. R., Korzenik, J. R., Rioux, J. D., Daly, M. J., Xavier, R. J., et al. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1000548 · Cited by 416 · see citing works
Ramonet, D., Daher, J. P. L., Lin, B. M., Stafa, K., Kim, J., Banerjee, R., Westerlund, M., Pletnikova, O., Glauser, L., Yang, L., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0018568 · Cited by 405 · see citing works
Eugenin, E. A., Osiecki, K., Lopez, L., Goldstein, H., Calderon, T. M., & Berman, J. W. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.3863-05.2006 · Cited by 392 · see citing works
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 · see citing works
Inhibition of Microglial Phagocytosis Is Sufficient To Prevent Inflammatory Neuronal Death
Neher, J. J., Neniskyte, U., Zhao, J.-W., Bal-Price, A., Tolkovsky, A. M., & Brown, G. C. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1003600 · Cited by 373 · see citing works
An immortalized cell line expresses properties of activated microglial cells
Bocchini, V., Mazzolla, R., Barluzzi, R., Blasi, E., Sick, P., & Kettenmann, H. (1992) · Journal of Neuroscience Research · doi:10.1002/jnr.490310405 · Cited by 364 · see citing works
Liu, Z., Lee, J., Krummey, S. M., Lü, W., Cai, H., & Lenardo, M. J. (2011) · Nature Immunology · doi:10.1038/ni.2113 · Cited by 361 · see citing works
Phosphatidylserine recognition by phagocytes: a view to a kill
Wu, Y., Tibrewal, N., & Birge, R. B. (2006) · Trends in Cell Biology · doi:10.1016/j.tcb.2006.02.003 · Cited by 341 · see citing works
Eaten alive! Cell death by primary phagocytosis: ‘phagoptosis’
Brown, G. C., & Neher, J. J. (2012) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2012.05.002 · Cited by 320 · see citing works
Friedman, L. G., Lachenmayer, M. L., Wang, J., He, L., Poulose, S. M., Komatsu, M., Holstein, G. R., & Yue, Z. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.5809-11.2012 · Cited by 303 · see citing works
Hakimi, M., Selvanantham, T., Swinton, E., Padmore, R., Tong, Y., Kabbach, G., Venderová, K., Girardin, S. E., Bulman, D. E., Scherzer, C. R., et al. (2011) · Journal of Neural Transmission · doi:10.1007/s00702-011-0653-2 · Cited by 284 · see citing works
Gillardon, F., Schmid, R. A., & Draheim, H. J. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2012.02.001 · Cited by 219 · see citing works
Dzamko, N. L., Iñesta-Vaquera, F., Zhang, J., Xie, C., Cai, H., Arthur, J. S. C., Tan, L., Choi, H., Gray, N. S., Cohen, P., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0039132 · Cited by 215 · see citing works
Neniškytė, U., Neher, J. J., & Brown, G. C. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.267583 · Cited by 208 · see citing works
Impaired Inflammatory Responses in Murine Lrrk2-Knockdown Brain Microglia
Kim, B., Yang, M.-S., Choi, D., Kim, J.-H., Kim, H.-S., Seol, W., Choi, S., Jou, I., Kim, E.-Y., & Joe, E.-H. (2012) · PLoS ONE · doi:10.1371/journal.pone.0034693 · Cited by 202 · see citing works
Inflammation in Parkinson's Disease
Tüfekçi, K. U., Meuwissen, R. L. J., Genç, Ş., & Genç, K. (2012) · Advances in protein chemistry and structural biology · doi:10.1016/b978-0-12-398314-5.00004-0 · Cited by 199 · see citing works
Chen, C.-Y., Weng, Y.-H., Chien, K.-Y., Lin, K.-J., Yeh, T.-H., Cheng, Y.-P., Lu, C.-S., & Wang, H.-L. (2012) · Cell Death and Differentiation · doi:10.1038/cdd.2012.42 · Cited by 189 · see citing works
Kure, K., Lyman, W. D., Weidenheim, K. M., & Dickson, D. W. (1990) · PubMed Central · Cited by 186 · see citing works
Adult neurogenesis and neurite outgrowth are impaired in LRRK2 G2019S mice
Winner, B., Melrose, H. L., Zhao, C. N., Hinkle, K. M., Yue, M., Kent, C., Braithwaite, A. T., Ogholikhan, S., Aigner, R., Winkler, J., et al. (2010) · Neurobiology of Disease · doi:10.1016/j.nbd.2010.12.008 · Cited by 183 · see citing works
Primary Phagocytosis of Neurons by Inflamed Microglia: Potential Roles in Neurodegeneration
Neher, J. J., Neniškytė, U., & Brown, G. C. (2012) · Frontiers in Pharmacology · doi:10.3389/fphar.2012.00027 · Cited by 151 · see citing works
El‐Hage, N., Wu, G., Wang, J. A., Ambati, J., Knapp, P. E., Reed, J. L., Bruce‐Keller, A. J., & Hauser, K. F. (2005) · Glia · doi:10.1002/glia.20262 · Cited by 151 · see citing works
Role of Tat Protein in HIV Neuropathogenesis
Li, W., Li, G., Steiner, J. P., & Nath, A. (2009) · Neurotoxicity Research · doi:10.1007/s12640-009-9047-8 · Cited by 148 · see citing works
Kim, H. J., Martemyanov, K. A., & Thayer, S. A. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.2958-08.2008 · Cited by 146 · see citing works
Anderson, E., Zink, W. E., Xiong, H., & Gendelman, H. E. (2002) · JAIDS Journal of Acquired Immune Deficiency Syndromes · doi:10.1097/00126334-200210012-00004 · Cited by 142 · see citing works
Gloeckner, C. J., Boldt, K., von Zweydorf, F., Helm, S., Wiesent, L., Sarioglu, H., & Ueffing, M. (2010) · Journal of Proteome Research · doi:10.1021/pr9008578 · Cited by 139 · see citing works
Meixner, A., Boldt, K., Troys, M. V., Askenazi, M., Gloeckner, C. J., Bauer, M., Marto, J. A., Ampè, C., Kinkl, N., & Ueffing, M. (2010) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m110.001172 · Cited by 131 · see citing works
Leucine‐rich repeat kinase 2 (LRRK2): A key player in the pathogenesis of Parkinson's disease
Gandhi, P. N., Chen, S. G., & Wilson‐Delfosse, A. L. (2008) · Journal of Neuroscience Research · doi:10.1002/jnr.21949 · Cited by 124 · see citing works
Kawakami, F., Takatoshi, Y., Ohta, E., Maekawa, T., Shimada, N., Suzuki, M., Maruyama, H., Ichikawa, T., & Obata, F. (2012) · PLoS ONE · doi:10.1371/journal.pone.0030834 · Cited by 122 · see citing works
Anatomical localization of leucine-rich repeat kinase 2 in mouse brain
Melrose, H. L., Lincoln, S. J., Tyndall, G., Dickson, D. W., & Farrer, M. J. (2006) · Neuroscience · doi:10.1016/j.neuroscience.2006.01.017 · Cited by 120 · see citing works
Rac1 Protein Rescues Neurite Retraction Caused by G2019S Leucine-rich Repeat Kinase 2 (LRRK2)
Chan, D., Citro, A., Cordy, J. M., Shen, G. C., & Wolozin, B. L. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.234005 · Cited by 120 · see citing works
Apoptotic Cells Induce a Phosphatidylserine-Dependent Homeostatic Response from Phagocytes
Kiss, R. S., Elliott, M. R., Ma, Z., Marcel, Y. L., & Ravichandran, K. S. (2006) · Current Biology · doi:10.1016/j.cub.2006.09.043 · Cited by 119 · see citing works
Neurocognitive dysfunction in the highly active antiretroviral therapy era
Mothobi, N. Z., & Brew, B. J. (2011) · Current Opinion in Infectious Diseases · doi:10.1097/qco.0b013e32834ef586 · Cited by 113 · see citing works
Immunocytochemistry and quantification of protein colocalization in cultured neurons
Glynn, M. W., & McAllister, A. K. (2006) · Nature Protocols · doi:10.1038/nprot.2006.220 · Cited by 101 · see citing works
Lu, S., Tremblay, M., King, I. L., Qi, J., Reynolds, H. M., Marker, D. F., Varrone, J. J., Majewska, A. K., Dewhurst, S., & Gelbard, H. A. (2011) · PLoS ONE · doi:10.1371/journal.pone.0023915 · Cited by 70 · see citing works
Self-citationBuscemi, L., Ramonet, D., & Geiger, J. D. (2007) · Neurobiology of Disease · doi:10.1016/j.nbd.2007.03.004 · Cited by 68 · see citing works
Rudenko, I. N., Chia, R., & Cookson, M. (2012) · BMC Medicine · doi:10.1186/1741-7015-10-20 · Cited by 64 · see citing works
Sui, Z., Fan, S., Sniderhan, L. F., Reisinger, E., Stout, A., Schifitto, G., Gelbard, H. A., Dewhurst, S., & Maggirwar, S. B. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.1.702 · Cited by 52 · see citing works
Self-citationIn vivo expression of proinflammatory cytokines in HIV encephalitis: an analysis of 11 autopsy cases
Xing, H. Q., Hayakawa, H., Izumo, K., Kubota, R., Gelpí, E., Budka, H., & Izumo, S. (2009) · Neuropathology · doi:10.1111/j.1440-1789.2008.00996.x · Cited by 50 · see citing works
Biochemical and molecular features of LRRK2 and its pathophysiological roles in Parkinson's disease
Seol, W. (2010) · BMB Reports · doi:10.5483/bmbrep.2010.43.4.233 · Cited by 48 · see citing works
Parkinson’s disease and immune system: is the culprit LRRKing in the periphery?
Greggio, E., Civiero, L., Bisaglia, M., & Bubacco, L. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-94 · Cited by 42 · see citing works
HIV-1 TAT inhibits microglial phagocytosis of Abeta peptide.
(2008) · PubMed Central · Cited by 37 · see citing works
Cowley, D., Gray, L. R., Wesselingh, S. L., Gorry, P. R., & Churchill, M. J. (2010) · Journal of NeuroVirology · doi:10.1007/s13365-010-0002-5 · Cited by 31 · see citing works
Dynamics of actin filaments in microglia during Fc receptor-mediated phagocytosis
Abd‐El‐Basset, E. M., & FEDOROFF, S. (1994) · Acta Neuropathologica · doi:10.1007/bf00296489 · Cited by 19 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Microglial Phagocytosis of Live Neurons
Brown, G. C., & Neher, J. J. (2014) · Nature Reviews Neuroscience · doi:10.1038/nrn3710 · Cited by 853 · see citing works
Brown, G. C., & Vilalta, A. (2015) · Brain Research · doi:10.1016/j.brainres.2015.08.031 · Cited by 306 · see citing works
Microglial phagocytosis of neurons in neurodegeneration, and its regulation
Butler, C. A., Popescu, A. S., Kitchener, E. J. A., Allendorf, D. H., Puigdellívol, M., & Brown, G. C. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15327 · Cited by 293 · see citing works
Microglial phenotypes in Parkinson’s disease and animal models of the disease
Joers, V., Tansey, M. G., Mulas, G., & Carta, A. R. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2016.04.006 · Cited by 285 · see citing works
Arcuri, C., Mecca, C., Bianchi, R., Giambanco, I., & Donato, R. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00191 · Cited by 279 · see citing works
Microglia in Parkinson's disease
Ho, M. S. (2019) · Advances in Experimental Medicine and Biology · doi:10.1007/978-981-13-9913-8_13 · Cited by 227 · see citing works
Membrane recruitment of endogenous LRRK2 precedes its potent regulation of autophagy
Schapansky, J., Nardozzi, J. D., Felizia, F., & LaVoie, M. J. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu138 · Cited by 226 · see citing works
Phagocytic microglia and macrophages in brain injury and repair
Yu, F., Wang, Y., Stetler, R. A., Leak, R. K., Hu, X., & Chen, J. (2022) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.13899 · Cited by 209 · see citing works
The Role of LRRK2 in Neurodegeneration of Parkinson Disease
Rui, Q., Ni, H., Li, D., Gao, R., & Chen, G. (2018) · Current Neuropharmacology · doi:10.2174/1570159x16666180222165418 · Cited by 196 · see citing works
The role of autophagy in modulation of neuroinflammation in microglia
Su, P., Zhang, J., Wang, D., Zhao, F., Cao, Z., Aschner, M., & Luo, W. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2016.01.035 · Cited by 183 · see citing works
LRRK2 and neuroinflammation: partners in crime in Parkinson’s disease?
Russo, I., Bubacco, L., & Greggio, E. (2014) · Journal of Neuroinflammation · doi:10.1186/1742-2094-11-52 · Cited by 180 · see citing works
LRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages
Härtlová, A., Herbst, S., Peltier, J., Rodgers, A., Bilkei‐Gorzo, O., Fearns, A., Dill, B. D., Lee, H., Flynn, R., Cowley, S. A., et al. (2018) · The EMBO Journal · doi:10.15252/embj.201798694 · Cited by 175 · see citing works
Copas, A. N. M., McComish, S. F., Fletcher, J. M., & Caldwell, M. A. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.666737 · Cited by 175 · see citing works
Glial phagocytic clearance in Parkinson’s disease
Tremblay, M., Cookson, M., & Civiero, L. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0314-8 · Cited by 159 · see citing works
Cai, Q., Li, Y., & Pei, G. (2017) · Journal of Neuroinflammation · doi:10.1186/s12974-017-0839-0 · Cited by 154 · see citing works
LRRK2: Cause, Risk, and Mechanism
Paisán‐Ruiz, C., Lewis, P. A., & Singleton, A. (2013) · Journal of Parkinson s Disease · doi:10.3233/jpd-130192 · Cited by 151 · see citing works
Neher, J. J., Neniškytė, U., Hornik, T. C., & Brown, G. C. (2014) · Glia · doi:10.1002/glia.22693 · Cited by 143 · see citing works
Astrocytes, Microglia, and Parkinson’s Disease
Joe, E.-H., Choi, D., An, J., Eun, J.-H., Jou, I., & Park, S.-M. (2018) · Experimental Neurobiology · doi:10.5607/en.2018.27.2.77 · Cited by 142 · see citing works
The complex relationships between microglia, alpha-synuclein, and LRRK2 in Parkinson's disease
Schapansky, J., Nardozzi, J. D., & LaVoie, M. J. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2014.09.049 · Cited by 132 · see citing works
Roles and functions of HIV-1 Tat protein in the CNS: an overview
Bagashev, A., & Sawaya, B. E. (2013) · Virology Journal · doi:10.1186/1743-422x-10-358 · Cited by 131 · see citing works
Russo, I., Berti, G., Plotegher, N., Bernardo, G., Filograna, R., Bubacco, L., & Greggio, E. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0449-7 · Cited by 128 · see citing works
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Streubel-Gallasch, L., Giusti, V., Sandre, M., Tessari, I., Plotegher, N., Giusto, E., Masato, A., Iovino, L., Battisti, I., Arrigoni, G., et al. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02327-8 · Cited by 123 · see citing works
Kim, K. S., Marcogliese, P. C., Yang, J., Callaghan, S. M., Resende, V., Abdel-Messih, E., Marras, C., Visanji, N. P., Huang, J., Schlossmacher, M. G., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1718946115 · Cited by 111 · see citing works
Ho, D. H., Je, A. R., Lee, H.-J., Son, I., Kweon, H., Kim, H., & Seol, W. (2018) · Experimental Neurobiology · doi:10.5607/en.2018.27.3.171 · Cited by 96 · see citing works
Fate of microglia during HIV‐1 infection: From activation to senescence?
Chen, N. C., Partridge, A. T., Sell, C., Torres, C. A., & Martín‐García, J. (2016) · Glia · doi:10.1002/glia.23081 · Cited by 93 · see citing works
Immune Responses in Parkinson’s Disease: Interplay between Central and Peripheral Immune Systems
Su, X., & Federoff, H. J. (2014) · BioMed Research International · doi:10.1155/2014/275178 · Cited by 91 · see citing works
Goodfellow, V. S., Loweth, C. J., Ravula, S. B., Wiemann, T., Nguyen, T. T., Xu, Y., Todd, D. E., Sheppard, D. W., Pollack, S. J., Polesskaya, O., et al. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm401094t · Cited by 88 · see citing works
Self-citationLRRK2 mediates microglial neurotoxicity via NFATc2 in rodent models of synucleinopathies
Kim, C., Beilina, A., Smith, N., Li, Y., Kim, M., Kumaran, R., Kaganovich, A., Mamais, A., Adame, A., Iba, M., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aay0399 · Cited by 79 · see citing works
Lee, H., Flynn, R., Sharma, I., Haberman, E. R., Carling, P. J., Nicholls, F. J., Stegmann, M., Vowles, J., Haenseler, W., Wade‐Martins, R., et al. (2020) · Stem Cell Reports · doi:10.1016/j.stemcr.2020.04.001 · Cited by 79 · see citing works
Moehle, M. S., Daher, J. P. L., Hull, T. D., Boddu, R., Abdelmotilib, H., Mobley, J. A., Kannarkat, G. T., Tansey, M. G., & West, A. B. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv157 · Cited by 73 · see citing works
Russo, I., Kaganovich, A., Ding, J., Landeck, N., Mamais, A., Varanita, T., Biosa, A., Tessari, I., Bubacco, L., Greggio, E., et al. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.05.012 · Cited by 68 · see citing works
Luerman, G. C., Nguyen, C., Samaroo, H., Loos, P., Xi, H. S., Hurtado‐Lorenzo, A., Needle, E., Noell, G. S., Galatsis, P., Dunlop, J., et al. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12483 · Cited by 63 · see citing works
Marker, D. F., Tremblay, M., Puccini, J. M., Barbieri, J., Marker, M. A. G., Loweth, C. J., Muly, E. C., Lu, S., Goodfellow, V. S., Dewhurst, S., et al. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.0598-13.2013 · Cited by 63 · see citing works
Self-citationRole of LRRK2 in manganese-induced neuroinflammation and microglial autophagy
Chen, J., Su, P., Luo, W., & Chen, J. (2018) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.02.007 · Cited by 61 · see citing works
The cross-talk of HIV-1 Tat and methamphetamine in HIV-associated neurocognitive disorders
Mediouni, S., Marcondes, M. C. G., Miller, C. A., McLaughlin, J. P., & Valente, S. T. (2015) · Frontiers in Microbiology · doi:10.3389/fmicb.2015.01164 · Cited by 60 · see citing works
Dzamko, N. L. (2017) · Advances in neurobiology · doi:10.1007/978-3-319-49969-7_7 · Cited by 60 · see citing works
Puccini, J. M., Marker, D. F., Fitzgerald, T., Barbieri, J., Kim, C. S., Miller‐Rhodes, P., Lu, S., Dewhurst, S., & Gelbard, H. A. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.0650-14.2015 · Cited by 59 · see citing works
Self-citationInvolvement of the Rabies Virus Phosphoprotein Gene in Neuroinvasiveness
Yamaoka, S., Ito, N., Ohka, S., Kaneda, S., Nakamura, H., Agari, T., Masatani, T., Nakagawa, K., Okada, K., Okadera, K., et al. (2013) · Journal of Virology · doi:10.1128/jvi.02132-13 · Cited by 55 · see citing works
Effect of LRRK2 protein and activity on stimulated cytokines in human monocytes and macrophages
Rastegar, D. A., Hughes, L. P., Perera, G., Keshiya, S., Zhong, S., Gao, J., Halliday, G. M., Schüle, B., & Dzamko, N. L. (2022) · npj Parkinson s Disease · doi:10.1038/s41531-022-00297-9 · Cited by 49 · see citing works
Dwyer, Z., Rudyk, C., Thompson, A., Farmer, K., Fenner, B. M., Fortin, T., Derksen, A., Sun, H., & Hayley, S. P. (2020) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2020.02.017 · Cited by 46 · see citing works
LRRK2 as a target for modulating immune system responses
Russo, I., Bubacco, L., & Greggio, E. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105724 · Cited by 45 · see citing works
miR-335 Targets LRRK2 and Mitigates Inflammation in Parkinson’s Disease
Oliveira, S. R., Dionísio, P. A., Gaspar, M. M., Guedes, L. C., Coelho, M. M., Rosa, M. M., Ferreira, J. J., Amaral, J. D., & Rodrigues, C. M. P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.661461 · Cited by 42 · see citing works
RetractedPajarillo, E. A. B., Rizor, A., Lee, J., Aschner, M., & Lee, E.-S. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2018.11.017 · Cited by 39 · see citing works
Miao, Y., & Meng, H. (2024) · Cell Communication and Signaling · doi:10.1186/s12964-023-01402-y · Cited by 37 · see citing works
Basic Concept of Microglia Biology and Neuroinflammation in Relation to Psychiatry
Mattei, D., & Notter, T. (2019) · Current topics in behavioral neurosciences · doi:10.1007/7854_2018_83 · Cited by 37 · see citing works
Cross-talk between LRRK2 and PKA: implication for Parkinson's disease?
Greggio, E., Bubacco, L., & Russo, I. (2017) · Biochemical Society Transactions · doi:10.1042/bst20160396 · Cited by 36 · see citing works
Neniškytė, U., Fricker, M., & Brown, G. C. (2016) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2016.06.005 · Cited by 35 · see citing works
Swimming short fibrous nasal drops achieving intraventricular administration
Wang, J., Wang, Q., Fu, Y., Lü, M., Chen, L., Liu, Z., Du, X., Du, X., Yu, B., Lu, H., et al. (2024) · 中国科学通报：英文版 · doi:10.1016/j.scib.2024.03.013 · Cited by 33 · see citing works
Integrated network analysis reveals new genes suggesting COVID-19 chronic effects and treatment
Pavel, A., del Giudice, G., Federico, A., Lieto, A. D., Kinaret, P., Serra, A., & Greco, D. (2020) · Briefings in Bioinformatics · doi:10.1093/bib/bbaa417 · Cited by 33 · see citing works
Effects of LRRK2 Inhibitors on Nigrostriatal Dopaminergic Neurotransmission
Qin, Q., Zhi, L., Li, X., Yue, Z., Li, G., & Zhang, H. (2016) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.12660 · Cited by 33 · see citing works
LRRK2 kinase inhibition protects against Parkinson's disease-associated environmental toxicants
Ilieva, N. M., Hoffman, E. K., Ghalib, M., Greenamyre, J. T., & Miranda, B. R. D. (2024) · Neurobiology of Disease · doi:10.1016/j.nbd.2024.106522 · Cited by 32 · see citing works
Miller‐Rhodes, P., Kong, C., Baht, G. S., Saminathan, P., Rodriguiz, R. M., Wetsel, W. C., Gelbard, H. A., & Terrando, N. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1582-5 · Cited by 32 · see citing works
Self-citationOligodendrocyte Injury and Pathogenesis of HIV-1-Associated Neurocognitive Disorders
Liu, H., Xu, E., Liu, J., & Xiong, H. (2016) · Brain Sciences · doi:10.3390/brainsci6030023 · Cited by 30 · see citing works
Dihydropyrimidinase-like 3 regulates the inflammatory response of activated microglia
Manivannan, J., Tay, S. S. W., Ling, E.-A., & Dheen, S. T. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.08.023 · Cited by 33 · see citing works
Mutti, V., Carini, G., Filippini, A., Castrezzati, S., Giugno, L., Gennarelli, M., & Russo, I. (2023) · Cells · doi:10.3390/cells12131799 · Cited by 27 · see citing works
Hajjo, R., Sabbah, D. A., Abusara, O. H., Kharmah, R., & Bardaweel, S. K. (2023) · Viruses · doi:10.3390/v15020568 · Cited by 26 · see citing works
G2019s LRRK2 promotes mitochondrial fission and increases TNFα-mediated neuroinflammation responses
Ho, D. H., Lee, H., Son, I., & Seol, W. (2019) · Animal Cells and Systems · doi:10.1080/19768354.2019.1585948 · Cited by 23 · see citing works
Mathema, V. B., & Na‐Bangchang, K. (2017) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2017.01.006 · Cited by 22 · see citing works
Moon, S. Y., Shin, S.-A., Oh, Y., Park, H. H., & Lee, C. S. (2018) · Genes · doi:10.3390/genes9120597 · Cited by 21 · see citing works
Emerging roles of protein kinases in microglia-mediated neuroinflammation
Lee, S. H., & Suk, K. (2017) · Biochemical Pharmacology · doi:10.1016/j.bcp.2017.06.137 · Cited by 21 · see citing works
Speidel, A., Felk, S., Reinhardt, P., Sterneckert, J. L., & Gillardon, F. (2016) · PLoS ONE · doi:10.1371/journal.pone.0165949 · Cited by 20 · see citing works
Kritzinger, A., Ferger, B., Gillardon, F., Stierstorfer, B., Birk, G., Kochanek, S., & Ciossek, T. (2018) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2018.02.008 · Cited by 20 · see citing works
Chen, L., Yang, Y., Li, C.-T., Zhang, S.-R., Zheng, W., Wei, E.-Q., & Zhang, L. (2015) · Brain Research · doi:10.1016/j.brainres.2015.08.007 · Cited by 19 · see citing works
Blasco-Agell, L., Pons‐Espinal, M., Testa, V., Roch, G., Montero-Muñoz, J., Fernández‐Carasa, I., Baruffi, V., González-Sepúlveda, M., Richaud‐Patín, Y., Jiménez‐Delgado, S., et al. (2025) · Communications Biology · doi:10.1038/s42003-025-08544-4 · Cited by 16 · see citing works
Zhang, M., Li, C., Ren, J., Wang, H., Fang, Y., Wu, J., & Tang, Y. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.909303 · Cited by 16 · see citing works
The microglial P2Y6 receptor as a therapeutic target for neurodegenerative diseases
Dundee, J. M., & Brown, G. C. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00438-5 · Cited by 14 · see citing works
Marker, D. F., Lu, S., & Gelbard, H. A. (2014) · Springer eBooks · doi:10.1007/978-1-4939-1429-6_15 · Cited by 14 · see citing works
Self-citationLRRK2 Kinase Inhibition Attenuates Astrocytic Activation in Response to Amyloid β1-42 Fibrils
Filippini, A., Salvi, V., Dattilo, V., Magri, C., Castrezzati, S., Veerhuis, R., Bosisio, D., Gennarelli, M., & Russo, I. (2023) · Biomolecules · doi:10.3390/biom13020307 · Cited by 13 · see citing works
Feng, L., Lo, H., Hong, Z., Zheng, J., Yan, Y., Ye, Z., Chen, X., & Pan, X. (2023) · Glia · doi:10.1002/glia.24422 · Cited by 12 · see citing works
Leucine-rich repeat kinase 2-related functions in GLIA: an update of the last years
Filippini, A., Gennarelli, M., & Russo, I. (2021) · Biochemical Society Transactions · doi:10.1042/bst20201092 · Cited by 10 · see citing works
Exploring the focal role of LRRK2 kinase in Parkinson’s disease
Kumar, S., Behl, T., Sehgal, A., Chigurupati, S., Singh, S., Mani, V., Aldubayan, M. A., Alhowail, A., Kaur, S., Bhatia, S., et al. (2022) · Environmental Science and Pollution Research · doi:10.1007/s11356-022-19082-5 · Cited by 8 · see citing works
LRRK2 G2019S and Parkinson’s disease: insight from Neuroinflammation
Yao, X.-Y., Guan, L.-N., Chen, Q., & Ren, C. (2023) · Postgraduate Medical Journal · doi:10.1093/postmj/qgad080 · Cited by 7 · see citing works
Navarro, E., Efthymiou, A. G., Mattei, D., Parks, M., Riboldi, G. M., Vialle, R. A., Udine, E., Muller, B. Z., Humphrey, J., Allan, A., et al. (2026) · Journal of Neuroinflammation · doi:10.1186/s12974-026-03967-0 · Cited by 6 · see citing works
Mamais, A., Wallings, R. L., & Rocha, E. M. (2023) · Handbook of clinical neurology · doi:10.1016/b978-0-323-85555-6.00009-6 · Cited by 6 · see citing works
Microglia in the Physiology and Pathology of Brain
Nagayach, A., Patro, N., & Patro, I. K. (2015) · Proceedings of the National Academy of Sciences India Section B Biological Sciences · doi:10.1007/s40011-015-0585-y · Cited by 6 · see citing works
Evaluation of Neuroinflammatory Contribution to Neurodegeneration in LRRK2 Drosophila Models
Nguyen, H. N., Galleri, G., Rassu, A. L., Ciampelli, C., Bernardoni, R., Galioto, M., Albani, D., Crosio, C., & Iaccarino, C. (2024) · Biomedicines · doi:10.3390/biomedicines12071555 · Cited by 4 · see citing works
Formation of templated inclusions in a forebrain α-synuclein mouse model is independent of LRRK2
Dues, D. J., Ma, Y., Nguyen, A. P. T., Offerman, A. V., Beddows, I., & Moore, D. J. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106338 · Cited by 4 · see citing works
Li, H., Terrando, N., & Gelbard, H. A. (2024) · Advances in neurobiology · doi:10.1007/978-3-031-55529-9_24 · Cited by 4 · see citing works
Self-citationGruol, D. L. (2017) · MDPI eBooks · doi:10.3390/books978-3-03842-571-7 · Cited by 1 · see citing works
Visualization of HIV-Associated Neurocognitive Disorders
Fitzgerald, T. (2016) · RIT Scholar Works (Rochester Institute of Technology)
HAND Adjunctive Therapies: Reversing Neuronal Injury
Marker, D. F., Fitzgerald, T., & Gelbard, H. A. (2015) · Springer eBooks · doi:10.1007/978-1-4614-9610-6_217-1
Self-citationElucidation of the cell signaling pathways mediating innate immunity and host-pathogen interactions
Nabar, N. R. (2019) · Figshare
HAND Adjunctive Therapies: Reversing Neuronal Injury
Marker, D. F., Fitzgerald, T., & Gelbard, H. A. (2018) · Springer eBooks · doi:10.1007/978-1-4939-7101-5_217
Self-citationChen, M., Sheng, Z.-H., Wang, L., Zhang, P., Zhang, J., Wang, X., Duan, J., Yang, W., Initiative, A. D. N., Yu, W., et al. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-05580-3
Zhao, Y., Wang, W., Li, S., Li, M. T., Zhang, W., Lu, T., Wang, L., Han, T., & Ren, W. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1856481
Synthetic viral RNA mimetics induce neuronal loss through microglial phagocytosis
Pampuščenko, K., Jankevičiūtė, S., Umbrasas, D., & Borutaitė, V. (2026) · Inflammation Research · doi:10.1007/s00011-026-02357-9
BindingDB (2014) · UC San Diego · doi:10.7270/q2p270ks
- Authors
- Marker, D. F., Puccini, J. M., Mockus, T. E., Barbieri, J., Lu, S.-M., & Gelbard, H. A.
- Affiliations
- University of Rochester Medicine (US)
- Corresponding author
- Marker, Daniel F
- Puccini, Jenna M
- Venue
- Journal of Neuroinflammation
- Published
- 2012-11-29
- Volume
- 9
- Issue
- 1
- Pages
- 261-261
- ISSN
- 1742-2094 (ISSN-L)
- PMC
- PMC3538654
- OpenAlex
- W2117667168
- Cited by
- 90
- References
- 61
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 6 · 2023: 7 · 2022: 5 · 2021: 5 · 2020: 4 · 2019: 9 · 2018: 11 · 2017: 7 · 2016: 9 · 2015: 8 · 2014: 7 · 2013: 7
- FWCI
- 3.71
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Journal of Neuroinflammation (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute of Mental Health (P01 MH 64570, F32MH099913, P01MH064570, R01 MH 56838, F30MH095664, R01MH056838)
- National Institute of General Medical Sciences (T32GM007356)
- National Institute of Allergy and Infectious Diseases (T32 AI 49815, T32AI049815, P30AI078498)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Health Sciences › Medicine › Surgery › Infectious Diseases and Tuberculosis
- Keywords
- LRRK2, HIV-1 Tat protein, microglial phagocytosis, HIV-associated neurocognitive disorders, LRRK2 kinase inhibition, microglial activation, inflammatory cytokines, microfluidic chamber
- MeSH terms
- Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Analysis of Variance, Animals, Axons, Cell Line, Transformed, Cytoplasm, Enzyme Inhibitors, Hippocampus, Humans, Microspheres, Neurons, Phagocytosis, Phosphorylation, RNA, Messenger, Serine, HIV-1, Gene Expression Regulation, Viral, Cytokines, Annexin A5, Protein Serine-Threonine Kinases, Microglia, Coculture Techniques, CD11b Antigen, Microfluidic Analytical Techniques, Mice, tat Gene Products, Human Immunodeficiency Virus
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