Cited by 132Parkinson's Disease Mechanisms and TreatmentsNeuroinflammation and Neurodegeneration MechanismsNuclear Receptors and Signaling

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The complex relationships between microglia, alpha-synuclein, and LRRK2 in Parkinson's disease

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Schapansky, J., Nardozzi, J.D., LaVoie, M.J.·2015·Neuroscience

DOI 10.1016/j.neuroscience.2014.09.049PMC PMC4383729

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Abstract

The proteins alpha-synuclein (αSyn) and leucine rich repeat kinase 2 (LRRK2) are both key players in the pathogenesis of the neurodegenerative disorder Parkinson's disease (PD), but establishing a functional link between the two proteins has proven elusive. Research studies for these two proteins have traditionally and justifiably focused in neuronal cells, but recent studies indicate that each protein could play a greater pathological role elsewhere. αSyn is expressed at high levels within neurons, but they also secrete the protein into the extracellular milieu, where it can have broad ranging effects in the nervous system and relevance to disease etiology. Similarly, low neuronal LRRK2 expression and activity suggests that LRRK2-related functions could be more relevant in cells with higher expression, such as brain-resident microglia. Microglia are monocytic immune cells that protect neurons from noxious stimuli, including pathological αSyn species, and microglial activation is believed to contribute to neuroinflammation and neuronal death in PD. Interestingly, both αSyn and LRRK2 can be linked to microglial function. Secreted αSyn can directly activate microglia, and can be taken up by microglia for clearance, while LRRK2 has been implicated in the intrinsic regulation of microglial activation and of lysosomal degradation processes. Based on these observations, the present review will focus on how PD-associated mutations in LRRK2 could potentially alter microglial biology with respect to neuronally secreted αSyn, resulting in cell dysfunction and neurodegeneration.

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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 434
Pre‐fibrillar α‐synuclein variants with impaired β‐structure increase neurotoxicity in Parkinson's disease models
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Ageing, neurodegeneration and Parkinson's disease
Hindle, J. V. (2010) · Age and Ageing · doi:10.1093/ageing/afp223 · Cited by 430
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 427
Microglial inflammation in the parkinsonian substantia nigra: relationship to alpha-synuclein deposition
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A critical evaluation of the Braak staging scheme for Parkinson's disease
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MHCII Is Required for -Synuclein-Induced Activation of Microglia, CD4 T Cell Proliferation, and Dopaminergic Neurodegeneration
Harms, A. S., Cao, S., Rowse, A. L., Thome, A. D., Li, X., Mangieri, L. R., Cron, R. Q., Shacka, J. J., Raman, C., & Standaert, D. G. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.5610-12.2013 · Cited by 406
A leaky blood–brain barrier, fibrinogen infiltration and microglial reactivity in inflamed Alzheimer’s disease brain
Ryu, J. K., & McLarnon, J. G. (2009) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2008.00434.x · Cited by 406
14-3-3 binding to LRRK2 is disrupted by multiple Parkinson's disease-associated mutations and regulates cytoplasmic localization
Nichols, R. J., Dzamko, N. L., Morrice, N. A., Campbell, D. G., Deák, M., Ordureau, A., Macartney, T., Tong, Y., Shen, J., Prescott, A. R., et al. (2010) · Biochemical Journal · doi:10.1042/bj20100483 · Cited by 390
Targeted Overexpression of Human α-Synuclein Triggers Microglial Activation and an Adaptive Immune Response in a Mouse Model of Parkinson Disease
Theodore, S., Cao, S., McLean, P. J., & Standaert, D. G. (2008) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e31818e5e99 · Cited by 388
Inhibition of LRRK2 kinase activity leads to dephosphorylation of Ser910/Ser935, disruption of 14-3-3 binding and altered cytoplasmic localization
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
The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease
Liu, Z., Lee, J., Krummey, S. M., Lü, W., Cai, H., & Lenardo, M. J. (2011) · Nature Immunology · doi:10.1038/ni.2113 · Cited by 374
LRRK2 protein levels are determined by kinase function and are crucial for kidney and lung homeostasis in mice
Herzig, M. C., Kolly, C., Persohn, E., Theil, D. J., Schweizer, T., Hafner, T., Stemmelen, C., Troxler, T. J., Schmid, P., Danner, S., et al. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr348 · Cited by 371
Neuron–glia crosstalk in health and disease: fractalkine and CX 3 CR1 take centre stage
Sheridan, G. K., & Murphy, K. J. (2013) · Open Biology · doi:10.1098/rsob.130181 · Cited by 358
Clearance and deposition of extracellular α-synuclein aggregates in microglia
Lee, H.-J., Suk, J.-E., Bae, E.-J., & Lee, S.-J. (2008) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2008.05.045 · Cited by 343
LRRK2 Controls an EndoA Phosphorylation Cycle in Synaptic Endocytosis
Matta, S., Van Kolen, K., da Cunha, R., van den Bogaart, G., Mandemakers, W., Miskiewicz, K., De Bock, P.-J., Morais, V. A., Vilain, S., Haddad, D., et al. (2012) · Neuron · doi:10.1016/j.neuron.2012.08.022 · Cited by 337
The Role of Innate and Adaptive Immunity in Parkinson's Disease
Kannarkat, G. T., Boss, J. M., & Tansey, M. G. (2013) · Journal of Parkinson’s Disease · doi:10.3233/jpd-130250 · Cited by 324
Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP
Gómez‐Suaga, P., Luzón-Toro, B., Churamani, D., Zhang, L., Bloor-Young, D., Patel, S., Woodman, P. G., Churchill, G. C., & Hilfiker, S. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr481 · Cited by 317
Alpha-synuclein and Protein Degradation Systems: a Reciprocal Relationship
Xilouri, M., Brekk, O. R., & Stefanis, L. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8341-2 · Cited by 310
Widespread Alterations of α-Synuclein in Multiple System Atrophy
Dickson, D. W., Liu, W.-K., Hardy, J., Farrer, M. J., Mehta, N. D., Uitti, R. J., Mark, M. H., Zimmerman, T., Golbe, L. I., Sage, J., et al. (1999) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)65226-1 · Cited by 298
Parkinson’s disease-linked LRRK2 is expressed in circulating and tissue immune cells and upregulated following recognition of microbial structures
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
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Cerebrospinal fluid lysosomal enzymes and alpha‐synuclein in Parkinson's disease
Parnetti, L., Chiasserini, D., Persichetti, E., Eusebi, P., Varghese, S., Qureshi, M. M., Dardis, A., Deganuto, M., Carlo, C. D., Castrioto, A., et al. (2014) · Movement Disorders · doi:10.1002/mds.25772 · Cited by 273
Toll-Like Receptor 4 Promotes α-Synuclein Clearance and Survival of Nigral Dopaminergic Neurons
Stefanova, N., Fellner, L., Reindl, M., Masliah, E., Poewe, W., & Wenning, G. K. (2011) · The American Journal of Pathology · doi:10.1016/j.ajpath.2011.04.013 · Cited by 272
Alpha-synuclein cell-to-cell transfer and seeding in grafted dopaminergic neurons in vivo
Angot, E., Steiner, J. A., Lema Tomé, C. M., Ekström, P., Mattsson, B., Björklund, A., & Brundin, P. (2012) · PLoS ONE · doi:10.1371/journal.pone.0039465 · Cited by 270
Enhancing Immunity Through Autophagy
Münz, C. (2008) · Annual Review of Immunology · doi:10.1146/annurev.immunol.021908.132537 · Cited by 269
α-Synuclein Activates Microglia by Inducing the Expressions of Matrix Metalloproteinases and the Subsequent Activation of Protease-Activated Receptor-1
Lee, E.-J., Woo, M.-S., Moon, P., Baek, M., Choi, I.-Y., Kim, W.-K., Junn, E., & Kim, H.-S. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0903480 · Cited by 267
Transfer of human α-synuclein from the olfactory bulb to interconnected brain regions in mice
Rey, N. L., Petit, G. H., Bousset, L., Melki, R., & Brundin, P. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1160-3 · Cited by 267
Microglia Acquire Distinct Activation Profiles Depending on the Degree of α-Synuclein Neuropathology in a rAAV Based Model of Parkinson's Disease
Sanchez-Guajardo, V., Febbraro, F., Kirik, D., & Romero-Ramos, M. (2010) · PLoS ONE · doi:10.1371/journal.pone.0008784 · Cited by 256
Microglia:Neuroprotective and Neurotrophic Cells in the Central Nervous System
Nakajima, K., & Kohsaka, S. (2004) · Cardiovascular & Haematological Disorders - Drug Targets · doi:10.2174/1568006043481284 · Cited by 256
Caudo‐rostral brain spreading of α‐synuclein through vagal connections
Ulusoy, A., Rusconi, R., Pérez‐Revuelta, B. I., Musgrove, R. E., Helwig, M., Winzen‐Reichert, B., & Monte, D. A. D. (2013) · EMBO Molecular Medicine · doi:10.1002/emmm.201302475 · Cited by 253
Neuroimmunological Processes in Parkinson’s Disease and their Relation to α-Synuclein: Microglia as the Referee between Neuronal Processes and Peripheral Immunity
Sánchez-Guajardo, V., Barnum, C. J., Tansey, M. G., & Romero‐Ramos, M. (2013) · ASN NEURO · doi:10.1042/an20120066 · Cited by 246
Tubulin Polymerization-promoting Protein (TPPP/p25α) Promotes Unconventional Secretion of α-Synuclein through Exophagy by Impairing Autophagosome-Lysosome Fusion
Ejlerskov, P., Rasmussen, I., Nielsen, T. T., Bergström, A., Tohyama, Y., Jensen, P. H., & Vilhardt, F. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.401174 · Cited by 242
Detection of elevated levels of soluble -synuclein oligomers in post-mortem brain extracts from patients with dementia with Lewy bodies
Paleologou, K. E., Kragh, C. L., Mann, D. M. A., Salem, S. A., Al‐Shami, R., Allsop, D., Hassan, A. H. M., Jensen, P. H., & El‐Agnaf, O. M. A. (2008) · Brain · doi:10.1093/brain/awn349 · Cited by 230
α-Synuclein activates stress signaling protein kinases in THP-1 cells and microglia
Klegeris, A., Pelech, S., Giasson, B. I., Maguire, J., Zhang, H., McGeer, E. G., & McGeer, P. L. (2008) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2006.11.013 · Cited by 227
Membrane Localization of LRRK2 Is Associated with Increased Formation of the Highly Active LRRK2 Dimer and Changes in Its Phosphorylation
Berger, Z., Smith, K. A., & LaVoie, M. J. (2010) · Biochemistry · doi:10.1021/bi100157u · Cited by 227
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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
Self-citation
Abrogation of α-synuclein–mediated dopaminergic neurodegeneration in LRRK2-deficient rats
Daher, J. P. L., Volpicelli-Daley, L. A., Blackburn, J. P., Moehle, M. S., & West, A. B. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1403215111 · Cited by 223
In Vivo Cross-linking Reveals Principally Oligomeric Forms of α-Synuclein and β-Synuclein in Neurons and Non-neural Cells
Dettmer, U., Newman, A. J., Luth, E. S., Bartels, T., & Selkoe, D. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.403311 · Cited by 221
Parkinson's disease-linked leucine-rich repeat kinase 2(R1441G) mutation increases proinflammatory cytokine release from activated primary microglial cells and resultant neurotoxicity
Gillardon, F., Schmid, R. A., & Draheim, H. J. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2012.02.001 · Cited by 219
Relationship between microglial activation and dopaminergic neuronal loss in the substantia nigra: a time course study in a 6‐hydroxydopamine model of Parkinson’s disease
Marinova‐Mutafchieva, L., Sadeghian, M., Broom, L., Davis, J. B., Medhurst, A. D., & Dexter, D. T. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06189.x · Cited by 217
The IkappaB Kinase Family Phosphorylates the Parkinson’s Disease Kinase LRRK2 at Ser935 and Ser910 during Toll-Like Receptor Signaling
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
Roles of the Drosophila LRRK2 homolog in Rab7-dependent lysosomal positioning
Dodson, M. W., Zhang, T., Jiang, C., Chen, S., & Guo, M. A. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr573 · Cited by 205
Autophagic failure promotes the exocytosis and intercellular transfer of α-synuclein
Lee, H.-J., Cho, E.-D., Lee, K., Kim, J., Cho, S., & Lee, S. (2013) · Experimental & Molecular Medicine · doi:10.1038/emm.2013.45 · Cited by 204
Substrate specificity and inhibitors of LRRK2, a protein kinase mutated in Parkinson's disease
Nichols, R. J., Dzamko, N. L., Hutti, J. E., Cantley, L. C., Deák, M., Moran, J., Bamborough, P., Reith, A. D., & Alessi, D. R. (2009) · Biochemical Journal · doi:10.1042/bj20091035 · Cited by 200
Neuron-glial interactions in blood-brain barrier formation.
Banerjee, S., & Bhat, M. (2007) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.30.051606.094345 · Cited by 199
Absence of α-synuclein mRNA expression in normal and multiple system atrophy oligodendroglia
Miller, D. W., Johnson, J. M., Solano, S. M., Hollingsworth, Z. R., Standaert, D. G., & Young, A. B. (2005) · Journal of Neural Transmission · doi:10.1007/s00702-005-0378-1 · Cited by 198
The influence of James and Darwin on Cajal and his research into the neuron theory and evolution of the nervous system
Ferreira, F. R. M., Nogueira, M. I., & DeFelipe, J. (2014) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2014.00001 · Cited by 196
Autophagy Regulates Phagocytosis by Modulating the Expression of Scavenger Receptors
Bonilla, D. L., Bhattacharya, A., Sha, Y., Xu, Y., Xiang, Q., Kan, A., Jagannath, C., Komatsu, M., & Eissa, N. T. (2013) · Immunity · doi:10.1016/j.immuni.2013.08.026 · Cited by 191
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 191
(G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD
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 191
Regulation of LRRK2 Expression Points to a Functional Role in Human Monocyte Maturation
Thévenet, J., Gobert, R. P., van Huijsduijnen, R. H., Wießner, C., & Sagot, Y. (2011) · PLoS ONE · doi:10.1371/journal.pone.0021519 · Cited by 191
LRRK2 knockout mice have an intact dopaminergic system but display alterations in exploratory and motor co-ordination behaviors
Hinkle, K. M., Yue, M., Behrouz, B., Dächsel, J. C., Lincoln, S., Bowles, E. E., Beevers, J. E., Dugger, B. N., Winner, B., Prots, I., et al. (2012) · Molecular Neurodegeneration · doi:10.1186/1750-1326-7-25 · Cited by 191
Protein aggregate spreading in neurodegenerative diseases: Problems and perspectives
Lee, S., Lim, H.-S., Masliah, E., & Lee, H.-J. (2011) · Neuroscience Research · doi:10.1016/j.neures.2011.05.008 · Cited by 190
Dopaminergic neuron loss and up‐regulation of chaperone protein mRNA induced by targeted over‐expression of alpha‐synuclein in mouse substantia nigra
Martin, J. L. S., Klucken, J., Outeiro, T. F., Nguyen, P. T., Keller-McGandy, C. E., Cantuti‐Castelvetri, I., Grammatopoulos, T. N., Standaert, D. G., Hyman, B. T., & McLean, P. J. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04310.x · Cited by 184
Microglial Activation and Antioxidant Responses Induced by the Parkinson’s Disease Protein α-Synuclein
Béraud, D., Hathaway, H. A., Trecki, J., Chasovskikh, S., Johnson, D. A., Johnson, J. A., Federoff, H. J., Shimoji, M., Mhyre, T. R., & Maguire‐Zeiss, K. A. (2012) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-012-9401-0 · Cited by 179
Loss of Leucine-Rich Repeat Kinase 2 (LRRK2) in Rats Leads to Progressive Abnormal Phenotypes in Peripheral Organs
Baptista, M. A. S., Dave, K. D., Frasier, M. A., Sherer, T., Greeley, M. A., Beck, M. J., Varsho, J. S., Parker, G. A., Moore, C., Churchill, M. J., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0080705 · Cited by 178
The LRRK2 G2019S mutant exacerbates basal autophagy through activation of the MEK/ERK pathway
Pedro, J. M. B., Niso‐Santano, M., Gómez‐Sánchez, R., Pizarro‐Estrella, E., Aiastui, A., Gorostidi, A., Climent, V. E., de Maturana, R. L., Sánchez‐Pernaute, R., de Munaín, A. L., et al. (2012) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-012-1061-y · Cited by 176
Transfer of host-derived alpha synuclein to grafted dopaminergic neurons in rat
Kordower, J. H., Dodiya, H. B., Kordower, A. M., Terpstra, B. T., Paumier, K. L., Madhavan, L., Sortwell, C. E., Steece‐Collier, K., & Collier, T. J. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.05.001 · Cited by 176
Phosphorylation-Dependent 14-3-3 Binding to LRRK2 Is Impaired by Common Mutations of Familial Parkinson's Disease
Li, X., Wang, Q. J., Pan, N., Lee, S., Zhao, Y., Chait, B. T., & Yue, Z. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017153 · Cited by 175
LRRK2 expression linked to dopamine‐innervated areas
Galter, D., Westerlund, M., Belin, A. C., Lindqvist, E., Sydow, O., & Olson, L. (2006) · Annals of Neurology · doi:10.1002/ana.20808 · Cited by 174
Phagocytic glial cells: sculpting synaptic circuits in the developing nervous system
Schafer, D. P., & Stevens, B. (2013) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2013.09.012 · Cited by 174
Neuron-Microglia Interaction in Neuroinflammation
Suzumura, A. (2013) · Current Protein & Peptide Science · doi:10.2174/1389203711314010004 · Cited by 173
LRRK2 G2019S Mutation Induces Dendrite Degeneration through Mislocalization and Phosphorylation of Tau by Recruiting Autoactivated GSK3β
Lin, C., Tsai, P.-I., Wu, R., & Chien, C. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.1737-10.2010 · Cited by 172
LRRK2 secretion in exosomes is regulated by 14-3-3
Fraser, K. B., Moehle, M. S., Daher, J. P. L., Webber, P. J., Williams, J. Y., Stewart, C. A., Yacoubian, T. A., Cowell, R. M., Dokland, T., Ye, T., et al. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt346 · Cited by 168
Autophagy Regulates IL-23 Secretion and Innate T Cell Responses through Effects on IL-1 Secretion
de Castro, C. P., Jones, S. A., Cheallaigh, C. N., Hearnden, C. H. A., Williams, L., Winter, J., Lavelle, E. C., Mills, K. H. G., & Harris, J. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1201946 · Cited by 167
Environmental stress, ageing and glial cell senescence: a novel mechanistic link to Parkinson's disease?
Chinta, S. J., Lieu, C. A., DeMaria, M., Laberge, R. ‐., Campisi, J., & Andersen, J. K. (2013) · Journal of Internal Medicine · doi:10.1111/joim.12029 · Cited by 165 · cited 2×
“, 2009; Barnett and Brewer, 2011; Cuervo and Macian, 2014), which is the single greatest risk factor in idiopathic PD (Hindle, 2010; Collier et al., 2011; Chinta et al., 2013).”
Background
Genetic variation in the autophagy gene ULK1 and risk of Crohnʼs disease
Henckaerts, L., Cleynen, I., Brinar, M., John, J. M., Steen, K. V., Rutgeerts, P. J., & Vermeire, S. (2010) · Inflammatory Bowel Diseases · doi:10.1002/ibd.21486 · Cited by 164
Assessment of α-Synuclein Secretion in Mouse and Human Brain Parenchyma
Emmanouilidou, E., Elenis, D., Papasilekas, T., Stranjalis, G., Gerozissis, K., Ioannou, P. C., & Vekrellis, K. (2011) · PLoS ONE · doi:10.1371/journal.pone.0022225 · Cited by 163
Skeletal muscle proteolysis in aging
Combaret, L., Dardevet, D. P., Béchet, D., Taillandier, D., Mosoni, L., & Attaix, D. (2008) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0b013e32831b9c31 · Cited by 162
Eat-Me: Autophagy, Phagocytosis, and Reactive Oxygen Species Signaling
Vernon, P. J., & Tang, D. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2012.4810 · Cited by 161
Microglial phagocytosis is enhanced by monomeric α‐synuclein, not aggregated α‐synuclein: Implications for Parkinson's disease
Park, J., Paik, S. R., Jou, I., & Park, S. M. (2008) · Glia · doi:10.1002/glia.20691 · Cited by 156
The acute inflammatory response to intranigral α-synuclein differs significantly from intranigral lipopolysaccharide and is exacerbated by peripheral inflammation
Couch, Y., Alvarez-Erviti, L., Sibson, N. R., Wood, M. J., & Anthony, D. C. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-166 · Cited by 155
α-Synuclein Expression Modulates Microglial Activation Phenotype
Austin, S. A., Floden, A. M., Murphy, E. J., & Combs, C. K. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.1799-06.2006 · Cited by 150
Demonstration of α-Synuclein Immunoreactivity in Neuronal and Glial Cytoplasm in Normal Human Brain Tissue Using Proteinase K and Formic Acid Pretreatment
Mori, F., Tanji, K., Yoshimoto, M., Takahashi, H., & Wakabayashi, K. (2002) · Experimental Neurology · doi:10.1006/exnr.2002.7929 · Cited by 149
Mutant α-Synuclein Overexpression Mediates Early Proinflammatory Activity
Su, X., Federoff, H. J., & Maguire-Zeiss, K. A. (2009) · Neurotoxicity Research · doi:10.1007/s12640-009-9053-x · Cited by 145
Total CSF α-synuclein is lower in de novo Parkinson patients than in healthy subjects
Mollenhauer, B., Trautmann, E., Taylor, P., Manninger, P., Sixel‐Döring, F., Ebentheuer, J., Trenkwalder, C., & Schlossmacher, M. G. (2012) · Neuroscience Letters · doi:10.1016/j.neulet.2012.11.004 · Cited by 143
LRRK2 delays degradative receptor trafficking by impeding late endosomal budding through decreasing Rab7 activity
Gómez-Suaga, P., Rivero-Ríos, P., Fdez, E., Blanca Ramírez, M., Ferrer, I., Aiastui, A., López De Munain, A., & Hilfiker, S. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu395 · Cited by 140
α-Synuclein Oligomers Impair Neuronal Microtubule-Kinesin Interplay
Prots, I., Veber, V., Brey, S., Campioni, S., Buder, K., Riek, R., Böhm, K. J., & Winner, B. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.451815 · Cited by 140
On the mechanism of internalization of α‐synuclein into microglia: roles of ganglioside GM1 and lipid raft
Park, J., Kim, K. S., Lee, S., Ryu, J., Chung, K. C., Choo, Y., Jou, I., Kim, J., & Park, S. M. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06150.x · Cited by 135
Differential LRRK2 expression in the cortex, striatum, and substantia nigra in transgenic and nontransgenic rodents
West, A. B., Cowell, R. M., Daher, J. P. L., Moehle, M. S., Hinkle, K. M., Melrose, H. L., Standaert, D. G., & Volpicelli‐Daley, L. A. (2014) · Journal of Comparative Neurology · doi:10.1002/cne.23583 · Cited by 134
Mutations in the LRRK2 Roc-COR tandem domain link Parkinson's disease to Wnt signalling pathways
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Rac1 Protein Rescues Neurite Retraction Caused by G2019S Leucine-rich Repeat Kinase 2 (LRRK2)
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Authors: Schapansky, J., Nardozzi, J. D., & LaVoie, M. J.
Affiliations: Brigham and Women's Hospital (US)
ORCID: Schapansky, J.
Nardozzi, J.D.
LaVoie, M.J.
Venue: Neuroscience
Publisher: Elsevier BV
Published: 2015-08
Volume: 302
Pages: 74-88
ISSN: 0306-4522 (ISSN-L)
DOI: 10.1016/j.neuroscience.2014.09.049
PMC: PMC4383729
OpenAlex: W1988160418
Cited by: 132
References: 212
Citations by year: 2026: 3 · 2025: 2 · 2024: 9 · 2023: 7 · 2022: 10 · 2021: 11 · 2020: 15 · 2019: 15 · 2018: 18 · 2017: 19 · 2016: 14 · 2015: 9
FWCI: 1.91
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Neuroscience (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Michael J. Fox Foundation
National Institutes of Health (NS072604)
Topics: Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
Keywords: Parkinson's disease, microglia, alpha-synuclein, LRRK2, microglial activation, neuroinflammation, extracellular alpha-synuclein, lysosomal degradation, LRRK2 mutations, neurodegeneration
MeSH terms: Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Animals, Humans, Parkinson Disease, Protein Serine-Threonine Kinases, Microglia, alpha-Synuclein

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The complex relationships between microglia, alpha-synuclein, and LRRK2 in Parkinson's disease

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