Aggregated α‐synuclein activates microglia: a process leading to disease progression in Parkinson's disease
Abstract
A growing body of evidence indicates that an inflammatory process in the substantia nigra, characterized by activation of resident microglia, likely either initiates or aggravates nigral neurodegeneration in Parkinson's disease (PD). To study the mechanisms by which nigral microglia are activated in PD, the potential role of alpha-synuclein (a major component of Lewy bodies that can cause neurodegeneration when aggregated) in microglial activation was investigated. The results demonstrated that in a primary mesencephalic neuron-glia culture system, extracellular aggregated human alpha-synuclein indeed activated microglia; microglial activation enhanced dopaminergic neurodegeneration induced by aggregated alpha-synuclein. Furthermore, microglial enhancement of alpha-synuclein-mediated neurotoxicity depended on phagocytosis of alpha-synuclein and activation of NADPH oxidase with production of reactive oxygen species. These results suggest that nigral neuronal damage, regardless of etiology, may release aggregated alpha-synuclein into substantia nigra, which activates microglia with production of proinflammatory mediators, thereby leading to persistent and progressive nigral neurodegeneration in PD. Finally, NADPH oxidase could be an ideal target for potential pharmaceutical intervention, given that it plays a critical role in alpha-synuclein-mediated microglial activation and associated neurotoxicity.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In some in vitro experiments, misfolded α-synuclein showed no toxicity to neurons unless microglia were present, indicating microglia activation may be crucial for toxicity of α-synuclein aggregates to neurons.
“In some in vitro experiments, misfolded α-synuclein showed no toxicity to neurons unless microglia were present, indicating that microglia activation may be crucial for the toxicity of α-synuclein aggregates to neurons.54,55”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [54]
Microglia release O2− or O2−-derived hydrogen peroxide when exposed to LPS, opsonized zymosan, or aggregated proteins that accumulate in the brain during neurodegenerative diseases.
“release O 2 ⅐Ϫ or O 2 ⅐Ϫ -derived hydrogen peroxide when exposed to LPS, opsonized zymosan, or aggregated proteins that accumulate in the brain during neurodegenerative diseases (Sankarapandi et al., 1998;Zhang et al., 2005;B. Qin et al., 2006;Wilkinson et al., 2006).”
From Neurotoxic Activation of Microglia Is Promoted by a Nox1-Dependent NADPH Oxidase (2008) · cites this paper as Zhang et al., 2005
One prevailing theory to explain synucleinopathies is that progressive alterations in the microenvironment of microglia, such as increased deposition of α-synuclein, can change microglial behavior and function.
“One prevailing theory to explain synucleinopathies is that progressive alterations in the microenvironment of microglia, such as increased deposition of α-synuclein, can change microglial behavior and function (Zhang et al., 2005; Su et al., 2008).”
From Microbiome–microglia connections via the gut–brain axis (2019) · cites this paper as Zhang et al., 2005
The sustained activation of microglia due to external cues from both misfolded α-synuclein and damaged neurons likely instigates a cycle of chronic inflammation that further perpetuates the death of dopaminergic neurons and accelerates progression of the disease.
“The sustained activation of microglia due to external cues from both misfolded α-synuclein and damaged neurons likely instigates a cycle of chronic inflammation that further perpetuates the death of dopaminergic neurons and accelerates progression of the disease (Zhang et al., 2005; Kim and Joh, 2006).”
From Microbiome–microglia connections via the gut–brain axis (2019) · cites this paper as Zhang et al., 2005
Heightened microglial activation results in the release of pro-inflammatory cytokines (e.g., IL-6 and TNF-α) and a variety of other neurotoxic compounds into their immediate extracellular environment.
“Heightened microglial activation results in the release of pro-inflammatory cytokines (e.g., IL-6 and TNF-α) and a variety of other neurotoxic compounds into their immediate extracellular environment (Zhang et al., 2005; Kim and Joh, 2006).”
From Microbiome–microglia connections via the gut–brain axis (2019) · cites this paper as Zhang et al., 2005
Cites
Free radicals in biology and medicine
Gutteridge, J. M. C. (1991) · General Pharmacology The Vascular System · doi:10.1016/0306-3623(91)90478-o · Cited by 17,178 · see citing works
Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids
Green, L. C., Wagner, D. A., Glogowski, J. A., Skipper, P. L., Wishnok, J. S., & Tannenbaum, S. R. (1982) · Analytical Biochemistry · doi:10.1016/0003-2697(82)90118-x · Cited by 12,089 · see citing works
Free Radicals in Biology and Medicine
Halliwell, B., & Gutteridge, J. M. C. (2015) · doi:10.1093/acprof:oso/9780198717478.001.0001 · Cited by 8,990 · see citing works
Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease
Polymeropoulos, M. H., Lavedan, C., Leroy, E., Ide, S. E., Dehejia, A., Dutra, A., Pike, B., Root, H., Rubenstein, J., Boyer, R., et al. (1997) · Science · doi:10.1126/science.276.5321.2045 · Cited by 8,240 · see citing works
α-Synuclein Locus Triplication Causes Parkinson's Disease
Singleton, A. B., Farrer, M., Johnson, J., Singleton, A., Hague, S., Kachergus, J., Hulihan, M., Peuralinna, T., Dutra, A., Nussbaum, R., et al. (2003) · Science · doi:10.1126/science.1090278 · Cited by 4,383 · see citing works
Self-citationAlaSOPro mutation in the gene encoding α-synuclein in Parkinson's disease
Krüger, R., Kuhn, W., Müller, T., Woitalla, D., Graeber, M., Kösel, S., Przuntek, H., Epplen, J. T., Schols, L., & Riess, O. (1998) · Nature Genetics · doi:10.1038/ng0298-106 · Cited by 3,836 · see citing works
McGeer, P. L., Itagaki, S., Boyes, B. E., & McGeer, E. G. (1988) · Neurology · doi:10.1212/wnl.38.8.1285 · Cited by 2,990 · see citing works
The new mutation, E46K, of α‐synuclein causes parkinson and Lewy body dementia
Zarranz, J. J., Alegre, J., Gómez‐Esteban, J. C., Lezcano, E., Ros, R., Ampuero, I., Vidal, L., Hoenicka, J., Rodriguez, O., Atarés, B., et al. (2004) · Annals of Neurology · doi:10.1002/ana.10795 · Cited by 2,737 · see citing works
BABIOR, B. M. (1999) · Blood · doi:10.1182/blood.v93.5.1464 · Cited by 2,147 · see citing works
Mice Lacking α-Synuclein Display Functional Deficits in the Nigrostriatal Dopamine System
Abeliovich, A., Schmitz, Y., Fariñas, I., Choi-Lundberg, D., Ho, W.-H., Castillo, P. E., Shinsky, N., Verdugo, J. M. G., Armanini, M., Ryan, A., et al. (2000) · Neuron · doi:10.1016/s0896-6273(00)80886-7 · Cited by 1,722 · see citing works
Molecular Pathways of Neurodegeneration in Parkinson's Disease
Dawson, T. M., & Dawson, V. L. (2003) · Science · doi:10.1126/science.1087753 · Cited by 1,659 · see citing works
Wu, D. C., Jackson-Lewis, V., Vila, M., Tieu, K., Teismann, P., Vadseth, C., Choi, D.-K., Ischiropoulos, H., & Przedborski, S. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-05-01763.2002 · Cited by 1,183 · see citing works
Kinetic Stabilization of the α-Synuclein Protofibril by a Dopamine-α-Synuclein Adduct
Conway, K. A., Rochet, J.-C., Bieganski, R. M., & Lansbury, P. T. (2001) · Science · doi:10.1126/science.1063522 · Cited by 1,127 · see citing works
Liu, B., & Hong, J.-S. (2003) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.102.035048 · Cited by 1,095 · see citing works
Self-citationShimura, H., Schlossmacher, M. G., Hattori, N., Frosch, M. P., Trockenbacher, A., Schneider, R., Mizuno, Y., Kosik, K. S., & Selkoe, D. J. (2001) · Science · doi:10.1126/science.1060627 · Cited by 1,053 · 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
Self-citationα-Synuclein Promotes Mitochondrial Deficit and Oxidative Stress
Hsu, L. J., Sagara, Y., Arroyo, A., Rockenstein, E. M., Sisk, A., Mallory, M. E., Wong, J., Takenouchi, T., Hashimoto, M., & Masliah, E. (2000) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)64553-1 · Cited by 716 · see citing works
Gao, H., Jiang, J., Wilson, B. C., Zhang, W., Hong, J., & Liu, B. (2002) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2002.00928.x · Cited by 690 · see citing works
Self-citationResistance of α-synuclein null mice to the parkinsonian neurotoxin MPTP
Dauer, W. T., Kholodilov, N. G., Vila, M., Trillat, A., Goodchild, R. E., Larsen, K. E., Staal, R. G. W., Tieu, K., Schmitz, Y., Yuan, C. A., et al. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.172514599 · Cited by 580 · see citing works
Qin, L., Liu, Y., Wang, T., Wei, S.-J., Block, M. L., Wilson, B., Liu, B., & Hong, J.-S. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m307657200 · Cited by 574 · see citing works
Self-citationAltered proteasomal function in sporadic Parkinson’s disease
St. P. McNaught, K., Belizaire, R., Isacson, O., Jenner, P., & Olanow, C. W. (2003) · Experimental Neurology · doi:10.1006/exnr.2002.8050 · Cited by 573 · see citing works
Sharon, R., Bar-Joseph, I., Frosch, M. P., Walsh, D. M., Hamilton, J. A., & Selkoe, D. J. (2003) · Neuron · doi:10.1016/s0896-6273(03)00024-2 · Cited by 562 · see citing works
Protein Nitration in Parkinsonʼs Disease
Good, P. F., Hsu, A., Werner, P., Perl, D. P., & Olanow, C. W. (1998) · Journal of Neuropathology and Experimental Neurology · doi:10.1097/00005072-199804000-00006 · Cited by 540 · see citing works
Bruyn, R. P. M. (2003) · Clinical Neurology and Neurosurgery · doi:10.1016/s0303-8467(02)00110-5 · Cited by 510 · see citing works
Inflammatory Regulators in Parkinson's Disease: iNOS, Lipocortin-1, and Cyclooxygenases-1 and -2
Knott, C., Stern, G., & Wilkin, G. P. (2000) · Molecular and Cellular Neuroscience · doi:10.1006/mcne.2000.0914 · Cited by 503 · see citing works
Tanaka, Y. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.9.919 · Cited by 497 · see citing works
Energetics in the pathogenesis of neurodegenerative diseases
Beal, M. F. (2000) · Trends in Neurosciences · doi:10.1016/s0166-2236(00)01584-8 · Cited by 472 · see citing works
Distinct Role for Microglia in Rotenone-Induced Degeneration of Dopaminergic Neurons
Gao, H., Hong, J., Zhang, W., & Liu, B. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-03-00782.2002 · Cited by 439 · see citing works
Self-citationTofaris, G. K., Layfield, R., & Spillantini, M. G. (2001) · FEBS Letters · doi:10.1016/s0014-5793(01)03115-5 · Cited by 363 · see citing works
Ding, T. T., Lee, S., Rochet, J., & Lansbury, P. T. (2002) · Biochemistry · doi:10.1021/bi020139h · Cited by 356 · see citing works
Critical Role for Microglial NADPH Oxidase in Rotenone-Induced Degeneration of Dopaminergic Neurons
Gao, H., Liu, B., & Hong, J. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-15-06181.2003 · Cited by 338 · see citing works
Self-citationWilms, H., Rosenstiel, P. C., Sievers, J., Deuschl, G., Zecca, L., & Lucius, R. (2003) · The FASEB Journal · doi:10.1096/fj.02-0314fje · Cited by 337 · see citing works
Mirza, B., Hadberg, H., Thomsen, P., & Moos, T. (1999) · Neuroscience · doi:10.1016/s0306-4522(99)00455-8 · Cited by 327 · see citing works
Qin, L., Liu, Y., Cooper, C. L., Liu, B., Wilson, B. C., & Hong, J. (2002) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2002.01210.x · Cited by 290 · see citing works
Self-citationGao, H., Hong, J., Zhang, W., & Liu, B. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-04-01228.2003 · Cited by 251 · see citing works
Self-citationIravani, M. M., Kashefi, K., Mander, P., Rose, S., & Jenner, P. (2002) · Neuroscience · doi:10.1016/s0306-4522(01)00562-0 · Cited by 247 · see citing works
Lewy bodies in Parkinson's disease are recognized by antibodies to complement proteins
Yamada, T., McGeer, P. L., & McGeer, E. G. (1992) · Acta Neuropathologica · doi:10.1007/bf00427222 · Cited by 231 · see citing works
Chapter 36: Astrocytes and Parkinson's disease
Forno, L. S., DeLanney, L. E., Irwin, I., Monte, D. A. D., & Langston, J. W. (1992) · Progress in brain research · doi:10.1016/s0079-6123(08)61770-7 · Cited by 230 · see citing works
Role of reactive oxygen species in LPS‐induced production of prostaglandin E2in microglia
Wang, T., Qin, L., Liu, B., Liu, Y., Wilson, B. C., Eling, T. E., Langenbach, R. I., Taniura, S., & Hong, J. (2004) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.02242.x · Cited by 218 · see citing works
Self-citationLiu, Y., Qin, L., Li, G., Zhang, W., An, L., Liu, B., & Hong, J. (2003) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.102.043166 · Cited by 205 · see citing works
Self-citationNeuroinflammatory perspectives on the two faces of Alzheimer?s disease
Eikelenboom, P., & van Gool, W. A. (2004) · Journal of Neural Transmission · doi:10.1007/s00702-003-0055-1 · Cited by 181 · see citing works
Liu, B., Jiang, J., Wilson, B. C., Du, L., Yang, S., Wang, J., Wu, G.-C., Cao, X.-D., & Hong, J. (2000) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)38877-9 · Cited by 167 · see citing works
Self-citationToll-Like Receptors and Inflammation in the CNS
Lee, B. S. P. S. J., & Lee, B. S. P. S. (2002) · Current Drug Targets - Inflammation & Allergy · doi:10.2174/1568010023344698 · Cited by 127 · see citing works
In vivo gene delivery of glial cell line-derived neurotrophic factor for Parkinson's disease
Kordower, J. H. (2003) · Annals of Neurology · doi:10.1002/ana.10485 · Cited by 120 · see citing works
Association of interleukin-1β polymorphisms with idiopathic Parkinson's disease
McGeer, P. L., Yasojima, K., & McGeer, E. G. (2002) · Neuroscience Letters · doi:10.1016/s0304-3940(02)00300-2 · Cited by 118 · see citing works
Cunningham, L. A., & Su, C. (2002) · Experimental Neurology · doi:10.1006/exnr.2002.7877 · Cited by 103 · see citing works
Mutant and Wild-Type α-Synuclein Interact with Mitochondrial Cytochrome C Oxidase
Elkon, H., Don, J., Melamed, E., Ziv, I., Shirvan, A., & Offen, D. (2002) · Journal of Molecular Neuroscience · doi:10.1385/jmn:18:3:229 · Cited by 103 · see citing works
Liu, Y., Qin, L., Wilson, B. C., An, L., Hong, J., & Liu, B. (2002) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.102.035956 · Cited by 94 · see citing works
Self-citationα-synuclein and cytosolic dopamine: Stabilizing a bad situation
Sulzer, D. L. (2001) · Nature Medicine · doi:10.1038/nm1201-1280 · Cited by 61 · see citing works
Lack of toxicity of human neuromelanin to rat brain dopaminergic neurons
Aimi, Y., & McGeer, P. L. (1996) · Parkinsonism & Related Disorders · doi:10.1016/1353-8020(96)00004-1 · Cited by 16 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Microglia-mediated neurotoxicity: uncovering the molecular mechanisms
Block, M. L., Zecca, L., & Hong, J.-S. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2038 · Cited by 4,110 · see citing works
Self-citationMechanisms underlying inflammation in neurodegeneration
Glass, C. K., Saijo, K., Winner, B., Marchetto, M. C., & Gage, F. H. (2010) · Cell · doi:10.1016/j.cell.2010.02.016 · Cited by 3,580 · see citing works
Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes
Kwon, H. S., & Koh, S.-H. (2020) · Translational Neurodegeneration · doi:10.1186/s40035-020-00221-2 · Cited by 2,595 · see citing works
The JAK/STAT signaling pathway: from bench to clinic
Hu, X., li, J., Fu, M., Zhao, X., & Wang, W. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00791-1 · Cited by 2,633 · see citing works
Pathological roles of MAPK signaling pathways in human diseases
Kim, E. K., & Choi, E.-J. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2009.12.009 · Cited by 2,472 · see citing works
Differential Roles of M1 and M2 Microglia in Neurodegenerative Diseases
Tang, Y., & Le, W. (2016) · Molecular Neurobiology · doi:10.1007/s12035-014-9070-5 · Cited by 2,190 · see citing works
Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration
Qin, L., Wu, X., Block, M. L., Liu, Y., Breese, G. R., Hong, J., Knapp, D. J., & Crews, F. T. (2007) · Glia · doi:10.1002/glia.20467 · Cited by 2,144 · see citing works
Self-citationThe Role of Oxidative Stress in Parkinson's Disease
Dias, V., Junn, E., & Mouradian, M. M. (2013) · Journal of Parkinson’s Disease · doi:10.3233/jpd-130230 · Cited by 1,845 · see citing works
Role of neuroinflammation in neurodegeneration development
Zhang, W., Xiao, D., Mao, Q., & Xia, H. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01486-5 · Cited by 1,668 · see citing works
Self-citationMicroglia in neurodegenerative diseases: mechanism and potential therapeutic targets
Gao, C., Jiang, J., Tan, Y., & Chen, S. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01588-0 · Cited by 1,616 · see citing works
Microglia and inflammation-mediated neurodegeneration: Multiple triggers with a common mechanism
Block, M. L., & Hong, J.-S. (2005) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2005.06.004 · Cited by 1,557 · see citing works
Self-citation-Synuclein in Parkinson's Disease
Stefanis, L. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a009399 · Cited by 1,446 · see citing works
Innate immune activation in neurodegenerative disease
Heneka, M. T., Kummer, M. P., & Latz, E. (2014) · Nature Reviews Immunology · doi:10.1038/nri3705 · Cited by 1,437 · see citing works
Inflammation and immune dysfunction in Parkinson disease
Tansey, M. G., Wallings, R. L., Houser, M. C., Herrick, M. K., Keating, C. E., & Joers, V. (2022) · Nature Reviews Immunology · doi:10.1038/s41577-022-00684-6 · Cited by 1,382 · see citing works
Dong, X.-X., Wang, Y., & Qin, Z.-H. (2009) · Acta Pharmacologica Sinica · doi:10.1038/aps.2009.24 · Cited by 1,297 · see citing works
Emmanouilidou, E., Melachroinou, K., Roumeliotis, T., Garbis, S. D., Ntzouni, M., Margaritis, L. H., Stefanis, L., & Vekrellis, K. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.5699-09.2010 · Cited by 1,115 · see citing works
Microglial Activation and Chronic Neurodegeneration
Lull, M. E., & Block, M. L. (2010) · Neurotherapeutics · doi:10.1016/j.nurt.2010.05.014 · Cited by 1,047 · see citing works
Self-citationOxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight
Bhat, A. H., Dar, K. B., Anees, S., Zargar, M. A., Masood, A., Sofi, M. A., & Ganie, S. A. (2015) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2015.07.025 · Cited by 938 · see citing works
Lee, H.-J., Suk, J.-E., Patrick, C., Bae, E.-J., Cho, J.-H., Rho, S., Hwang, D., Masliah, E., & Lee, S.-J. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.081125 · Cited by 877 · see citing works
Neuroinflammation in Parkinson's disease and its potential as therapeutic target
Wang, Q., Liu, Y., & Zhou, J. (2015) · Translational Neurodegeneration · doi:10.1186/s40035-015-0042-0 · Cited by 884 · see citing works
Microglia-mediated neuroinflammation in neurodegenerative diseases
Subhramanyam, C. S., Wang, C., Hu, Q., & Dheen, S. T. (2019) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2019.05.004 · Cited by 875 · see citing works
Kim, C., Ho, D.-H., Suk, J.-E., You, S., Michael, S., Kang, J., Joong Lee, S., Masliah, E., Hwang, D., Lee, H.-J., et al. (2013) · Nature Communications · doi:10.1038/ncomms2534 · Cited by 856 · see citing works
Exosomal cell-to-cell transmission of alpha synuclein oligomers
Danzer, K. M., Kranich, L. R., Ruf, W. P., Cagsal‐Getkin, O., Winslow, A. R., Zhu, L., Vanderburg, C. R., & McLean, P. J. (2012) · Molecular Neurodegeneration · doi:10.1186/1750-1326-7-42 · Cited by 852 · see citing works
Role of Oxidative Stress in Parkinson's Disease
Hwang, O. (2013) · Experimental Neurobiology · doi:10.5607/en.2013.22.1.11 · Cited by 845 · see citing works
Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression
Gao, H., & Hong, J. (2008) · Trends in Immunology · doi:10.1016/j.it.2008.05.002 · Cited by 822 · see citing works
Self-citationInflammation in Parkinson’s Disease: Mechanisms and Therapeutic Implications
Pajares, M., I. Rojo, A., Manda, G., Boscá, L., & Cuadrado, A. (2020) · Cells · doi:10.3390/cells9071687 · Cited by 779 · see citing works
Alpha-synuclein: Pathology, mitochondrial dysfunction and neuroinflammation in Parkinson’s disease
Rocha, E. M., Miranda, B. D., & Sanders, L. H. (2017) · Neurobiology of Disease · doi:10.1016/j.nbd.2017.04.004 · Cited by 769 · see citing works
Interrelation of Oxidative Stress and Inflammation in Neurodegenerative Disease: Role of TNF
Fischer, R., & Maier, O. (2015) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2015/610813 · Cited by 744 · see citing works
Glial reactions in Parkinson's disease
McGeer, P. L., & McGeer, E. G. (2008) · Movement Disorders · doi:10.1002/mds.21751 · Cited by 701 · see citing works
Toll‐like receptor 4 is required for α‐synuclein dependent activation of microglia and astroglia
Fellner, L., Irschick, R., Schanda, K., Reindl, M., Klimaschewski, L., Poewe, W., Wenning, G. K., & Stefanova, N. (2013) · Glia · doi:10.1002/glia.22437 · Cited by 697 · see citing works
Heterogeneity of CNS myeloid cells and their roles in neurodegeneration
Prinz, M., Priller, J., Sisodia, S. S., & Ransohoff, R. M. (2011) · Nature Neuroscience · doi:10.1038/nn.2923 · Cited by 674 · see citing works
Plasma exosomal α-synuclein is likely CNS-derived and increased in Parkinson’s disease
Shi, M., Liu, C., Cook, T. J., Bullock, K. M., Zhao, Y., Ginghina, C., Li, Y., Aro, P., Dator, R., He, C., et al. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1314-y · Cited by 676 · see citing works
Self-citationRole of Microglia in Neurotrauma
Loane, D. J., & Byrnes, K. R. (2010) · Neurotherapeutics · doi:10.1016/j.nurt.2010.07.002 · Cited by 657 · see citing works
Alternatively activated microglia and macrophages in the central nervous system
Franco, R., & Fernández‐Suárez, D. (2015) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.05.003 · Cited by 650 · see citing works
Phagocytosis of Microglia in the Central Nervous System Diseases
Fu, R., Shen, Q., Xu, P., Luo, J. J., & Tang, Y. (2014) · Molecular Neurobiology · doi:10.1007/s12035-013-8620-6 · Cited by 646 · see citing works
Inflammation as a causative factor in the aetiology of Parkinson's disease
Whitton, P. S. (2007) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0707167 · Cited by 625 · see citing works
Jiang, T., Sun, Q., & Chen, S. (2016) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2016.07.005 · Cited by 594 · see citing works
Triggering of inflammasome by aggregated α-synuclein, an inflammatory response in synucleinopathies
Codolo, G., Plotegher, N., Pozzobon, T., Brucale, M., Tessari, I., Bubacco, L., & de Bernard, M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0055375 · Cited by 585 · see citing works
Tansey, M. G., McCoy, M. K., & Frank-Cannon, T. C. (2007) · Experimental Neurology · doi:10.1016/j.expneurol.2007.07.004 · Cited by 580 · see citing works
Cell Biology and Pathophysiology of α-SynucleinPreprint
Burré, J., Sharma, M., & Südhof, T. C. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a024091 · Cited by 576 · see citing works
Microglia in Neuroinflammation and Neurodegeneration: From Understanding to Therapy
Muzio, L., Viotti, A., & Martino, G. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.742065 · Cited by 581 · see citing works
Microglial exosomes facilitate α-synuclein transmission in Parkinson’s disease
Guo, M., Wang, J., Zhao, Y., Feng, Y., Han, S., Dong, Q., Cui, M., & Tieu, K. (2020) · Brain · doi:10.1093/brain/awaa090 · Cited by 522 · see citing works
Lipopolysaccharide-induced neuroinflammation as a bridge to understand neurodegeneration
Batista, C. R. A., Gomes, G. F., Candelario-Jalil, E., Fiebich, B. L., & de Oliveira, A. C. P. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20092293 · Cited by 529 · see citing works
Microbiome–microglia connections via the gut–brain axis
Abdel-Haq, R., Schlachetzki, J. C. M., Glass, C. K., & Mazmanian, S. K. (2019) · Journal of Experimental Medicine · doi:10.1084/jem.20180794 · Cited by 471 · see citing works
Synuclein activates microglia in a model of Parkinson's disease
Su, X., Maguire-Zeiss, K. A., Giuliano, R., Prifti, L., Venkatesh, K., & Federoff, H. J. (2008) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.04.006 · Cited by 474 · see citing works
NOX Enzymes in the Central Nervous System: From Signaling to Disease
Sorce, S., & Krause, K. (2009) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.2578 · Cited by 472 · see citing works
Zhou, Y., Lu, M., Du, R.-H., Qiao, C., Jiang, C.-Y., Zhang, K.-Z., Ding, J.-H., & Hu, G. (2016) · Molecular Neurodegeneration · doi:10.1186/s13024-016-0094-3 · Cited by 455 · see citing works
Self-citationDefects in trafficking bridge Parkinson’s disease pathology and genetics
Abeliovich, A., & Gitler, A. D. (2016) · Nature · doi:10.1038/nature20414 · Cited by 462 · see citing works
The mechanisms of NLRP3 inflammasome/pyroptosis activation and their role in Parkinson's disease
Wang, S., Yuan, Y., Chen, N., & Wang, H. (2018) · International Immunopharmacology · doi:10.1016/j.intimp.2018.12.019 · Cited by 447 · see citing works
Assembly-dependent endocytosis and clearance of extracellular a-synuclein
Lee, H.-J., Suk, J.-E., Bae, E.-J., Lee, J.-H., Paik, S. R., & Lee, S.-J. (2008) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2008.01.017 · Cited by 470 · see citing works
Mhyre, T. R., Boyd, J. T., Hamill, R. W., & Maguire‐Zeiss, K. A. (2012) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-94-007-5416-4_16 · Cited by 442 · see citing works
Neuroinflammation and Oxidation/Nitration of α-Synuclein Linked to Dopaminergic Neurodegeneration
Gao, H., Kotzbauer, P. T., Uryu, K., Leight, S., Trojanowski, J. Q., & Lee, V. M. ‐. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.0143-07.2008 · Cited by 435 · see citing works
Oxidative stress and the pathogenesis of neurodegenerative disorders.
Reynolds, A. D., Laurie, C., Mosley, R., & Gendelman, H. (2007) · International review of neurobiology · doi:10.1016/s0074-7742(07)82016-2 · Cited by 443 · see citing works
NADPH oxidase in brain injury and neurodegenerative disorders
Ma, M. W., Wang, J., Zhang, Q., Wang, R., Dhandapani, K. M., Vadlamudi, R. K., & Brann, D. W. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0150-7 · Cited by 432 · see citing works
Glia: Initiators and progressors of pathology in Parkinson's disease
Halliday, G. M., & Stevens, C. H. (2011) · Movement Disorders · doi:10.1002/mds.23455 · Cited by 423 · see citing works
Neuroprotective activities of CD4+CD25+ regulatory T cells in an animal model of Parkinson’s disease
Reynolds, A. D., Banerjee, R., Liu, J., Gendelman, H. E., & Mosley, R. L. (2007) · Journal of Leukocyte Biology · doi:10.1189/jlb.0507296 · Cited by 422 · see citing works
Reynolds, A. D., Stone, D. K., Hutter, J. A. L., Benner, E., Mosley, R., & Gendelman, H. E. (2010) · Journal of Immunology · doi:10.4049/jimmunol.0901852 · Cited by 391 · see citing works
Microglia Mediated Neuroinflammation in Parkinson’s Disease
Işık, S., Yeman-Kıyak, B., Akbayır, R., Şeyhali-Abutayeh, R., & Arpaci, T. (2023) · Cells · doi:10.3390/cells12071012 · Cited by 402 · see citing works
Neuroinflammation and regulation of glial glutamate uptake in neurological disorders
Tilleux, S., & Hermans, E. (2007) · Journal of Neuroscience Research · doi:10.1002/jnr.21325 · Cited by 381 · see citing works
Alpha-Synuclein Oligomers—Neurotoxic Molecules in Parkinson's Disease and Other Lewy Body Disorders
Ingelsson, M. (2016) · Frontiers in Neuroscience · doi:10.3389/fnins.2016.00408 · Cited by 374 · see citing works
Gao, H.-M., Zhang, F., Zhou, H., Kam, W., Wilson, B., & Hong, J.-S. (2011) · Environmental Health Perspectives · doi:10.1289/ehp.1003013 · Cited by 355 · see citing works
“Exogenous application of aggregated α-syn activates cultured microglia (Zhang et al. 2005).”
BackgroundSelf-citationTissue macrophages: origin, heterogenity, biological functions, diseases and therapeutic targets
Guan, F., Wang, R., Yi, Z., Luo, P., Liu, W., Xie, Y., Liu, Z., Xia, Z., Zhang, H., & Cheng, Q. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02124-y · Cited by 371 · see citing works
Theodore, S., Cao, S., McLean, P. J., & Standaert, D. G. (2008) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e31818e5e99 · Cited by 367 · see citing works
Nitrated α–Synuclein Immunity Accelerates Degeneration of Nigral Dopaminergic Neurons
Benner, E. J., Banerjee, R., Reynolds, A. D., Sherman, S., Писарев, В. М., Tsiperson, V., Nemachek, C., Ciborowski, P. S., Przedborski, S., Mosley, R. L., et al. (2008) · PLoS ONE · doi:10.1371/journal.pone.0001376 · Cited by 359 · see citing works
Vegeto, E., Benedusi, V., & Maggi, A. C. (2008) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2008.04.001 · Cited by 356 · see citing works
Zipp, F., & Aktas, O. (2006) · Trends in Neurosciences · doi:10.1016/j.tins.2006.07.006 · Cited by 373 · see citing works
The Role of Oxidative Stress in Parkinson’s Disease
Chang, K., & Chen, C. (2020) · Antioxidants · doi:10.3390/antiox9070597 · Cited by 357 · see citing works
Microglia Phenotypes in Aging and Neurodegenerative Diseases
Wendimu, M. Y., & Hooks, S. B. (2022) · Cells · doi:10.3390/cells11132091 · Cited by 336 · see citing works
Alpha-synuclein oligomers: a new hope
Bengoa‐Vergniory, N., Roberts, R. F., Wade‐Martins, R., & Alegre‐Abarrategui, J. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1755-1 · Cited by 335 · see citing works
Ferroptosis and cell death mechanisms in Parkinson's disease
Guiney, S. J., Adlard, P. A., Bush, A. I., Finkelstein, D. I., & Ayton, S. (2017) · Neurochemistry International · doi:10.1016/j.neuint.2017.01.004 · Cited by 337 · see citing works
Mitochondrial association of alpha-synuclein causes oxidative stress
Parihar, M. S., Parihar, A., Fujita, M., Hashimoto, M., & Ghafourifar, P. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-008-7589-1 · Cited by 331 · see citing works
Microglia: gatekeepers of central nervous system immunology
Tambuyzer, B. R., Ponsaerts, P., & Nouwen, E. J. (2008) · Journal of Leukocyte Biology · doi:10.1189/jlb.0608385 · Cited by 331 · see citing works
CD4+ Regulatory and Effector/Memory T Cell Subsets Profile Motor Dysfunction in Parkinson’s Disease
Hutter-Saunders, J. A. L., Estes, K. A., Kosloski, L. M., Allen, H. E., Dempsey, K., Torres‐Russotto, D. R., Meza, J. L., Santamaria, P. M., Bertoni, J. M., Murman, D. L., et al. (2012) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-012-9402-z · Cited by 325 · see citing works
Chronic microglial activation and progressive dopaminergic neurotoxicity
Block, M. L., & Hong, J. (2007) · Biochemical Society Transactions · doi:10.1042/bst0351127 · Cited by 324 · see citing works
Self-citationClearance 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 · see citing works
Dopamine, Immunity, and Disease
Channer, B., Matt, S. M., Nickoloff-Bybel, E. A., Pappa, V., Agarwal, Y., Wickman, J. R., & Gaskill, P. J. (2022) · Pharmacological Reviews · doi:10.1124/pharmrev.122.000618 · Cited by 319 · see citing works
Daniele, S. G., Béraud, D., Davenport, C., Cheng, K., Yin, H., & Maguire-Zeiss, K. A. (2015) · Science Signaling · doi:10.1126/scisignal.2005965 · Cited by 303 · see citing works
Microglia, Lifestyle Stress, and Neurodegeneration
Madore, C., Yin, Z., Leibowitz, J. A., & Butovsky, O. (2020) · Immunity · doi:10.1016/j.immuni.2019.12.003 · Cited by 310 · see citing works
Redox Control of Microglial Function: Molecular Mechanisms and Functional Significance
Rojo, A. I., McBean, G. J., Cindrić, M., Egea, J., López, M. G., Rada, P., Žarković, N., & Cuadrado, A. (2014) · Antioxidants and Redox Signaling · doi:10.1089/ars.2013.5745 · Cited by 313 · see citing works
The identity and function of microglia in neurodegeneration
Song, W. M., & Colonna, M. (2018) · Nature Immunology · doi:10.1038/s41590-018-0212-1 · Cited by 308 · see citing works
The Therapeutic Potential of Metformin in Neurodegenerative Diseases
Rotermund, C., Machetanz, G., & Fitzgerald, J. C. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00400 · Cited by 310 · see citing works
Oxidative and Inflammatory Pathways in Parkinson’s Disease
Miller, R. L., James-Kracke, M., Sun, G. Y., & Sun, A. Y. (2009) · Neurochemical Research · doi:10.1007/s11064-008-9656-2 · Cited by 306 · see citing works
Extracellular α-synuclein—a novel and crucial factor in Lewy body diseases
Lee, H.-J., Bae, E.-J., & Lee, S. (2014) · Nature Reviews Neurology · doi:10.1038/nrneurol.2013.275 · Cited by 304 · see citing works
Magnetic Resonance Spectroscopy to Assess NeuroInflammation and Neuropathic Pain
Chang, L., Munsaka, S. M., Kraft-Terry, S. D., & Ernst, T. M. (2013) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-013-9460-x · Cited by 306 · see citing works
Neuroinflammation and oxidative stress: Co-conspirators in the pathology of Parkinson’s disease
Taylor, J. M., Main, B. S., & Crack, P. J. (2013) · Neurochemistry International · doi:10.1016/j.neuint.2012.12.016 · Cited by 303 · see citing works
The hallmarks of P arkinson's disease
Antony, P. M. A., Diederich, N. J., Krüger, R., & Balling, R. (2013) · FEBS Journal · doi:10.1111/febs.12335 · Cited by 301 · see citing works
Contributions of central and systemic inflammation to the pathophysiology of Parkinson's disease
Collins, L. M., Toulouse, A., Connor, T. J., & Nolan, Y. M. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.01.028 · Cited by 275 · see citing works
The influence of microglia on the pathogenesis of Parkinson's disease
Long-Smith, C. M., Sullivan, A. M., & Nolan, Y. M. (2009) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2009.08.001 · Cited by 296 · see citing works
Tilstra, J. S., Clauson, C. L., Niedernhofer, L. J., & Robbins, P. D. (2011) · Europe PMC (PubMed Central) · Cited by 290 · see citing works
Salehi, B., Sharifi-Rad, J., Cappellini, F., Reiner, Ž., Zorzan, D., Imran, M., Sener, B., Kilic, M., El-Shazly, M., Fahmy, N. M., et al. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.01300 · Cited by 293 · see citing works
Alpha-synuclein: from secretion to dysfunction and death
Marques, O., & Outeiro, T. F. (2012) · Cell Death and Disease · doi:10.1038/cddis.2012.94 · Cited by 287 · see citing works
Cellular Senescence in Neurodegenerative Diseases
Martínez‐Cué, C., & Rueda, N. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00016 · Cited by 285 · see citing works
Dzamko, N., Gysbers, A., Perera, G., Bahar, A., Shankar, A., Gao, J., Fu, Y., & Halliday, G. M. (2017) · Acta Neuropathologica · doi:10.1007/s00401-016-1648-8 · Cited by 273 · see citing works
The Contribution of Microglia to Neuroinflammation in Parkinson’s Disease
Badanjak, K., Fixemer, S., Smajić, S., Skupin, A., & Grünewald, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094676 · Cited by 281 · see citing works
Recent advances in our understanding of neurodegeneration
Jellinger, K. A. (2009) · Journal of Neural Transmission · doi:10.1007/s00702-009-0240-y · Cited by 274 · see citing works
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 · see citing works
Microglia, Amyloid, and Glucose Metabolism in Parkinson’s Disease with and without Dementia
Edison, P., Ahmed, I., Fan, Z., Hinz, R., Gelosa, G., Chaudhuri, К. R., Walker, Z., Turkheimer, F., & Brooks, D. J. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2012.255 · Cited by 275 · see citing works
Integrating Pathways of Parkinson's Disease in a Molecular Interaction Map
Fujita, K., Ostaszewski, M., Matsuoka, Y., Ghosh, S., Glaab, E., Trefois, C., Crespo, I., Perumal, T. M., Jurkowski, W., Antony, P. M. A., et al. (2013) · Molecular Neurobiology · doi:10.1007/s12035-013-8489-4 · Cited by 270 · see citing works
Qin, H., Buckley, J. A., Li, X., Liu, Y., Fox, T. H., Meares, G. P., Yu, H., Yan, Z., Harms, A. S., Li, Y., et al. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.4658-15.2016 · Cited by 275 · see citing works
Periphery and brain, innate and adaptive immunity in Parkinson’s disease
Harms, A. S., Ferreira, S. A., & Romero‐Ramos, M. (2021) · Acta Neuropathologica · doi:10.1007/s00401-021-02268-5 · Cited by 279 · see citing works
- Authors
- Zhang, W., Wang, T., Pei, Z., Miller, D. S., Wu, X., Block, M. L., Wilson, B., Zhang, W., Zhou, Y., Hong, J.-S., & Zhang, J.
- Affiliations
- National Institutes of Health (US)
- Dalian Medical University (CN)
- University of Washington (US)
- ORCID
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2005-04
- Volume
- 19
- Issue
- 6
- Pages
- 533-542
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W2128631317
- Cited by
- 1,265
- References
- 50
- Citations by year
- 2026: 30 · 2025: 57 · 2024: 95 · 2023: 51 · 2022: 97 · 2021: 80 · 2020: 69 · 2019: 76 · 2018: 85 · 2017: 51 · 2016: 59 · 2015: 71 · 2014: 67 · 2013: 60 · 2012: 69
- FWCI
- 23.37
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- alpha-synuclein aggregation, microglial activation, Parkinson's disease, substantia nigra, dopaminergic neuron loss, NADPH oxidase, reactive oxygen species, phagocytosis, neuroinflammation, Lewy bodies, neurotoxicity, disease progression
- MeSH terms
- Animals, Astrocytes, Brain, Cells, Cultured, Dopamine, Embryo, Mammalian, Enzyme Activation, gamma-Aminobutyric Acid, Humans, Immunohistochemistry, Mesencephalon, Nerve Degeneration, Neuroglia, Neurons, Nitric Oxide, Nitrites, Parkinson Disease, Phagocytosis, Polymers, Rats, Inbred F344, Recombinant Proteins, Substantia Nigra, Tritium, Tumor Necrosis Factor-alpha, Tyrosine 3-Monooxygenase, Dinoprostone, Reactive Oxygen Species, Microglia, Mice, Knockout, Oxidative Stress, NADPH Oxidases, Mice, Rats, alpha-Synuclein
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
