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Synuclein activates microglia in a model of Parkinson's disease
Open accessAbstract
Parkinson's disease (PD) is the most common neurodegenerative movement disorder afflicting >500,000 patients in the United States alone. This age-related progressive disorder is typified by invariant loss of dopaminergic substantia nigra neurons (DAN), dystrophic neurites, the presence of alpha-synuclein (SYN) positive intracytoplasmic inclusions (Lewy bodies) in the remaining DAN, and activated microglia. As such, microglial activation and resultant increase in proinflammatory molecules have moved to the forefront of PD research as a potential pathobiologic mechanism of disease. Herein, we present data demonstrating early microglial activation in mice that over-express wild-type SYN, the release of SYN from a SYN overexpressing MN9D cell line, and dose-dependent SYN-mediated activation of primary microglial cultures with consequent increases in proinflammatory molecules. Furthermore, we provide evidence that the CD36 scavenger receptor and downstream kinases are involved in SYN-mediated microglial activation. Together, our data suggest an early role for SYN and inflammation in PD pathogenesis.
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“SR-B2 promotes α-synuclein–microglial interactions64 and senses misfolded mutant or oxidized SOD1 in diseased motor neurons or in the extracellular space, rendering these cells proinflammatory85.”
From Microglia in neurodegeneration (2018) · cites this paper as [64]
In the citing paper
“Microglia accumulate near α-synuclein deposits and become proinflammatory in a manner dependent on receptors that also bind Aβ, such as CD36 and TLR263–65.”
From Microglia in neurodegeneration (2018) · cites this paper as [64]
In the citing paper
“Microglia also phagocytose α-synuclein, the constituent protein of Lewy bodies in Parkinson’s and Lewy Body dementias, and become pro-inflammatory in the process, expressing cytokines (IL1β, IL6, TNFα), reactive oxygen species (ROS) and prostaglandin synthesising cyclooxygenase 2 (COX2) [24,25,26].”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [25]
Citations
Cites
Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4
LAEMMLI, U. K. (1970) · Nature · doi:10.1038/227680a0 · Cited by 249,961
Raza, H., John, A., & Nemmar, A. (2013) · Cellular Physiology and Biochemistry · doi:10.1159/000350087 · Cited by 47,311
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
Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism
Kitada, T., Asakawa, S., Hattori, N., Matsumine, H., Yamamura, Y., Minoshima, S., Yokochi, M., Mizuno, Y., & Shimizu, N. (1998) · Nature · doi:10.1038/33416 · Cited by 5,227
Microglia: a sensor for pathological events in the CNS
Kreutzberg, G. W. (1996) · Trends in Neurosciences · doi:10.1016/0166-2236(96)10049-7 · Cited by 4,396
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
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
AlaSOPro 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
McGeer, P. L., Itagaki, S., Boyes, B. E., & McGeer, E. G. (1988) · Neurology · doi:10.1212/wnl.38.8.1285 · Cited by 2,990
Spillantini, M. G., Crowther, R. A., Jakes, R., Hasegawa, M., & Goedert, M. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.11.6469 · Cited by 2,868
Research works printed but not linked: 1
- Manning-Bog, 2001, The herbicide paraquat causes upregulation and aggregation of alpha-synuclein in mice, J. Biol. Chem., 13, 13
Cited by
Sorted by citations
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Hirsch, E. C., & Hunot, S. (2009) · The Lancet Neurology · doi:10.1016/s1474-4422(09)70062-6 · Cited by 1,984
The 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
“Similarly, exposure of primary microglial cells to recombinant aggregated or mutated alphasynuclein results in increased activated microglia and ROS production followed by the secretion of TNF-alpha, IL6 and IL-1beta [266] [272] [273] and the activation of intracellular pathways such as ERK1/2 and p38 MAPK [272].”
BackgroundMicroglia in neurodegeneration
Hickman, S., Izzy, S., Sen, P., Morsett, L., & El Khoury, J. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0242-x · Cited by 1,710
Role of Pro-Inflammatory Cytokines Released from Microglia in Neurodegenerative Diseases
Smith, J. A., Das, A., Ray, S. K., & Banik, N. L. (2012) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2011.10.004 · Cited by 1,165
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
“It has been reported that recombinant -synuclein can activate microglia cells (Zhang et al., 2005; Su et al., 2008).”
BackgroundSimpson, D. S. A., & Oliver, P. L. (2020) · Antioxidants · doi:10.3390/antiox9080743 · Cited by 1,044
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
“Wild-type or pathogenic forms of α-synuclein induces pronounced microglial activation in vitro [63].”
BackgroundLee, 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
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
Inflammation 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
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 801
Microglia: biology and pathology
Graeber, M. B., & Streit, W. J. (2009) · Acta Neuropathologica · doi:10.1007/s00401-009-0622-0 · Cited by 736
“In keeping with the view that microglia in PD are reactive rather than aggressive, synuclein has been found to stimulate microglia [174].”
BackgroundMicroglia in Neurological Diseases: A Road Map to Brain-Disease Dependent-Inflammatory Response
Bachiller, S., Jiménez-Ferrer, I., Paulus, A., Yang, Y., Swanberg, M., Deierborg, T., & Boza‐Serrano, A. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00488 · Cited by 750
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
“VC 2012 Wiley Periodicals, Inc. Reynolds et al., 2008; Rojanathammanee et al., 2011; Su et al., 2008).”
BackgroundTakata, F., Nakagawa, S., Matsumoto, J., & Dohgu, S. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.661838 · Cited by 651
Neuroinflammation in Parkinson's disease
Hirsch, E. C., Vyas, S., & Hunot, S. (2012) · Parkinsonism & Related Disorders · doi:10.1016/s1353-8020(11)70065-7 · Cited by 657
“This hypothesis is supported by several lines of evidence: (1) Overexpression of a-synuclein in animals leads to neuroinflammatory processes [14].”
ResultJiang, T., Sun, Q., & Chen, S. (2016) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2016.07.005 · Cited by 605
“Microglial cells are a dynamic immune cell population of the CNS. Evidence suggested that extracellular aggregated α-Syn activated microglia specifically (Su et al., 2008; Zhang et al., 2007).”
BackgroundTansey, M. G., McCoy, M. K., & Frank-Cannon, T. C. (2007) · Experimental Neurology · doi:10.1016/j.expneurol.2007.07.004 · Cited by 587
“…that mice that overexpress wild-type α-synuclein display early microglia activation and that α-synuclein release from an α-synuclein-overexpressing dopaminergic neuron-like cell line triggers a cascade of proinflammatory mediators that include TNF, IL-1β, IL-6, COX-2 and iNOS (Su et al., 2007).”
BackgroundInfluentialMicroglia 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
“Peripheral T cells can infiltrate the CNS of PD patients (Brochard et al., 2009), and interact with the α-synuclein protein, stimulating microglial activation – i.e., increase of MHC II levels – and eventually concurring to the demise of DA neurons as shown in a rat model (Subbarayan et al., 2020).”
BackgroundParkinson’s Disease: Etiology, Neuropathology, and Pathogenesis
Kouli, A., Torsney, K., & Kuan, W. (2018) · Codon Publications eBooks · doi:10.15586/codonpublications.parkinsonsdisease.2018.ch1 · Cited by 634
“For instance, in primary cultures, α-synuclein mediates a dose-dependent activation of microglia (154).”
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
Defects in trafficking bridge Parkinson’s disease pathology and genetics
Abeliovich, A., & Gitler, A. D. (2016) · Nature · doi:10.1038/nature20414 · Cited by 462
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 463
“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript Maguire-Zeiss et al. 2008; Reynolds et al. 2008; Su et al. 2008; Theodore et al. 2008; Su et al. 2009; Lee et al. 2010; Beraud et al. 2011).”
BackgroundSelf-citationLinking Neuroinflammation and Neurodegeneration in Parkinson's Disease
Gelders, G., Baekelandt, V., & Van der Perren, A. (2018) · Journal of Immunology Research · doi:10.1155/2018/4784268 · Cited by 430
“Microglial activation lymphocytic infiltration [66, 68, 69]”
BackgroundMicroglia 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 419
Theodore, S., Cao, S., McLean, P. J., & Standaert, D. G. (2008) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e31818e5e99 · Cited by 392
“Early activation of microglia is also present in a transgenic mouse model of PD in which wild-type human >-SYN is expressed under a tyrosine hydroxylase promoter (31).”
Vegeto, E., Benedusi, V., & Maggi, A. C. (2008) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2008.04.001 · Cited by 364
Targeting Microglial Activation States as a Therapeutic Avenue in Parkinson’s Disease
Subramaniam, S., & Federoff, H. J. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00176 · Cited by 353
Self-citationThe Role of Oxidative Stress in Parkinson’s Disease
Chang, K., & Chen, C. (2020) · Antioxidants · doi:10.3390/antiox9070597 · Cited by 369
Microglial Dynamics and Role in the Healthy and Diseased Brain: A Paradigm of Functional Plasticity
Gomez-Nicola, D., & Perry, V. H. (2015) · The Neuroscientist · doi:10.1177/1073858414530512 · Cited by 340
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“In response to these stimuli, microglia produce cytokines [59, 61, 62], reactive oxygen species [63, 64], prostanoids that have immunomodulatory functions [65], and chemokines that recruit peripheral immune cells [66, 67].”
BackgroundDaniele, 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
“2 ng endotoxin/ml], consistent with our previous reports (48, 52).”
BackgroundResultInfluentialSelf-citationMicroglial 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
“Similarly, one-month old TH α-synuclein mice displayed an increase of Iba1-positive ameboid shaped microglia in the SN and increased expression of TNF in both the SN and striatum (Su et al., 2008).”
BackgroundInfluentialHarischandra, D. S., Ghaisas, S., Zenitsky, G. D., Jin, H., Kanthasamy, A., Anantharam, V., & Kanthasamy, A. G. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00654 · Cited by 296
DAMPs as mediators of sterile inflammation in aging-related pathologies
Feldman, N., Rotter-Maskowitz, A., & Okun, E. (2015) · Ageing Research Reviews · doi:10.1016/j.arr.2015.01.003 · Cited by 283
“Importantly, -synuclein activates microglia through a mechanism that involves CD36; however other PRRs also seem to respond to -synuclein, as microglia derived from CD36 knockout mice are still activated following exposure to -synuclein, albeit to a lesser extent (Su et al., 2008, 2009).”
BackgroundTumor necrosis factor-alpha mediated signaling in neuronal homeostasis and dysfunction
Park, K. M., & Bowers, W. J. (2010) · Cellular Signalling · doi:10.1016/j.cellsig.2010.01.010 · Cited by 282
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
“Recent reports have suggested that α-synuclein is a DAMP, capable of modulating inflammatory cytokine production in microglia [1, 3, 21, 39, 47].”
BackgroundThe 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 296
“In addition, both, treatment of primary mouse microglia with α-synuclein and α-synuclein OE in mice, are known to give rise to microglial ROS, TNF-α, IL-1β, COX2, iNOS [82,83].”
BackgroundPeriphery 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 291
Jang, A., Lee, H., Suk, J., Jung, J., Kim, K., & Lee, S. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.06695.x · Cited by 281
“A number of studies have shown that extracellular a-synuclein can activate microglia in culture, inducing an inflammatory response (Klegeris et al. 2008; Reynolds et al. 2008; Su et al. 2008; Zhang et al. 2005).”
BackgroundThe role of Toll-like receptors and neuroinflammation in Parkinson’s disease
Heidari, A., Yazdanpanah, N., & Rezaei, N. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02496-w · Cited by 275
“Moreover, microglial activation was also observed in human α-synuclein-overexpressing transgenic mice [67].”
BackgroundLee, 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
“(20) found that CD36 (a microglial scavenger receptor) mediates ROS production, ERK phosphorylation, and proinflammatory cytokine expression in a-synuclein–stimulated microglia.”
BackgroundFyn kinase regulates misfolded α-synuclein uptake and NLRP3 inflammasome activation in microglia
Panicker, N., Sarkar, S., Harischandra, D. S., Neal, M. P., Kam, T., Jin, H., Saminathan, H., Langley, M. R., Charli, A., Samidurai, M., et al. (2019) · The Journal of Experimental Medicine · doi:10.1084/jem.20182191 · Cited by 256
“TLR4, CD36, and Fc γ R-deficient microglia have exhibited attenuated neuroinflammatory responses to α Syn treatment (Su et al., 2008; Cao et al., 2012; Fellner et al., 2013).”
Sanchez-Guajardo, V., Febbraro, F., Kirik, D., & Romero-Ramos, M. (2010) · PLoS ONE · doi:10.1371/journal.pone.0008784 · Cited by 256
“This relationship between a-syn and microglia activation has also been reported in vivo [50,51,62].”
BackgroundTargeting TNF-Alpha to Elucidate and Ameliorate Neuroinflammation in Neurodegenerative Diseases
Frankola, K. A., Greig, N. H., Luo, W., & Tweedie, D. (2011) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/187152711794653751 · Cited by 255
Watson, M. B., Richter, F., Lee, S., Gabby, L. C., Wu, J. E., Masliah, E., Effros, R. B., & Chesselet, M. (2012) · Experimental Neurology · doi:10.1016/j.expneurol.2012.06.025 · Cited by 254
“…expression can trigger microglial activation and cytokine production prior to the loss of dopaminergic neurons, suggesting that inflammation can contribute to the pathological process that eventually leads to cell death (Su et al., 2008; Theodore et al., 2008; Sanchez-Guajardo et al., 2010).”
BackgroundInfluentialSánchez-Guajardo, V., Barnum, C. J., Tansey, M. G., & Romero‐Ramos, M. (2013) · ASN NEURO · doi:10.1042/an20120066 · Cited by 246
“…subtype2 knockout Lack of EP2 abolished MPTP-induced ↑ aggregated α-syn In vitro EP2 knockout microglia has ↑ ability to clear α-syn Miller et al., 2007, Su et al., 2008, 2009 DM A30P-A53T * Overexpression under TH promoter Mouse C57/Bl6 ↑% of activated Iba-1 + cells in SN ↑mRNA TGFβ SN and…”
BackgroundInfluentialMicroglia in the CNS: Immigrants from another world
Prinz, M., & Mildner, A. (2010) · Glia · doi:10.1002/glia.21104 · Cited by 245
“The potential pathway leading to microglial activation comprises the MPTP-dependent production and release of misfolded a-synuclein by DN (Dauer and Przedborski, 2003), which in turn can activate microglia (Su et al., 2007; Zhang et al., 2005).”
BackgroundThe changing phenotype of microglia from homeostasis to disease
Luo, X., & Chen, S. (2012) · Translational Neurodegeneration · doi:10.1186/2047-9158-1-9 · Cited by 246
“α-synuclein Lee et al., 2010; Su et al., 2008; Zhang et al., 2005 [55-57] amyloid-beta Jana et al., 2008 [58] fibrinogen Piers et al., 2011 [59] Thrombin Lee et al., 2005 [60] Tissue plasminogen activator Siao et al., 2002 [61] Matrix protein (vitronectin, fibronectin, MMP-3) Milner et al., 2007;…”
BackgroundMicroglia 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
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Dzamko, N., Geczy, C. L., & Halliday, G. M. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2014.10.028 · Cited by 222
Microglia Response During Parkinson’s Disease: Alpha-Synuclein Intervention
Ferreira, S. A., & Romero‐Ramos, M. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00247 · Cited by 227
“Wake, H., Moorhouse, A. J., Miyamoto, A., and Nabekura, J. (2013). Microglia: actively surveying and shaping neuronal circuit structure and function.”
BackgroundMicroglia as modulators of exosomal alpha-synuclein transmission
Xia, Y. F., Zhang, G., Han, C., Ma, K., Guo, X., Wan, F. J., Kou, L., Yin, S., Liu, L., Huang, J., et al. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1404-9 · Cited by 212
Brkic, M., Balusu, S., Libert, C., & Vandenbroucke, R. E. (2015) · Mediators of Inflammation · doi:10.1155/2015/620581 · Cited by 205
“involved in alteration of α-synuclein protein conformation, thus contributing to aggregation, Lewy body formation, and microglial activation [227].”
BackgroundGlia and alpha-synuclein in neurodegeneration: A complex interaction
Brück, D., Wenning, G. K., Stefanova, N., & Fellner, L. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.03.003 · Cited by 213
“primary microglial cells causes a dose-dependent release of proinflammatory molecules (Klegeris et al., 2008; Su et al., 2008).”
M1 and M2 immune activation in Parkinson’s Disease: Foe and ally?
Moehle, M. S., & West, A. B. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.11.018 · Cited by 209
“Neuroscience (2014), TLR4 and CD11b, largely depending on the constituency of the protein aggregates applied to cells (Zhang et al., 2007; Su et al., 2008; Lee et al., 2010).”
BackgroundInfluentialα-Synuclein Alters Toll-Like Receptor Expression
Béraud, D., Twomey, M. A., Bloom, B., Mittereder, A., Ton, V., Neitzke, K., Chasovskikh, S., Mhyre, T. R., & Maguire‐Zeiss, K. A. (2011) · Frontiers in Neuroscience · doi:10.3389/fnins.2011.00080 · Cited by 203
“…leads to increased numbers of activated microglia in mouse models of α-synuclein overexpression prior to SNpc dopamine neuron death and has a direct effect on microglial activation in cell culture experiments (Zhang et al., 2005; Su et al., 2008, 2009; Theodore et al., 2008; Lee et al., 2010).”
BackgroundMethodInfluentialSelf-citationInflammation 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 205
Ten Unsolved Questions About Neuroinflammation in Parkinson's Disease
Hirsch, É. C., & Standaert, D. G. (2020) · Movement Disorders · doi:10.1002/mds.28075 · Cited by 196
Alpha-synuclein release by neurons activates the inflammatory response in a microglial cell line
Alvarez‐Erviti, L., Couch, Y., Richardson, J. C., Cooper, J. A. D., & Wood, M. J. A. (2011) · Neuroscience Research · doi:10.1016/j.neures.2010.12.020 · Cited by 199
“…activated microglial cells by interaction with cience C a i f c W m i e e 2 i M M t f e o f p r r t c p e s M s o w T t a o d A c m a r c M t t C A f R A B L. Alvarez-Erviti et al. / Neuros D36 receptor (Su et al., 2008), Mac-1 receptor (Zhang et al., 2007) nd other uncharacterised mechanisms.”
BackgroundResultChakraborty, R., Nonaka, T., Hasegawa, M., & Zurzolo, C. (2023) · Cell Death & Disease · doi:10.1038/s41419-023-05835-8 · Cited by 190
Neuroinflammation and Parkinson’s Disease—From Neurodegeneration to Therapeutic Opportunities
Araújo, B., Caridade-Silva, R., Soares-Guedes, C., Martins‐Macedo, J., Gomes, E. D., Monteiro, S., & Teixeira, F. G. (2022) · Cells · doi:10.3390/cells11182908 · Cited by 209
“Accordingly, in transgenic animal models with overexpression or mutation (A53T and A30P) of α-Syn, increased numbers of activated microglia and release of proinflammatory molecules were reported, showing that this process can occur before the degeneration of the DAn and the appearance of PD motor symptomatology [103,1…”
BackgroundKrashia, P., Cordella, A., Nobili, A., La Barbera, L., Federici, M., Leuti, A., Campanelli, F., Natale, G., Marino, G., Calabrese, V., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11928-w · Cited by 188
Exogenous α-synuclein induces toll-like receptor 4 dependent inflammatory responses in astrocytes
Rannikko, E. H., Weber, S. S., & Kahle, P. J. (2015) · BMC Neuroscience · doi:10.1186/s12868-015-0192-0 · Cited by 185
“with recombinant αSYN produced in bacteria as well as cell culture medium from cells that overexpress αSYN induces neuroinflammatory responses in microglia and astroglia [26, 27, 36–38].”
Enhanced Phosphatase Activity Attenuates α-Synucleinopathy in a Mouse Model
Lee, K.-W., Chen, W. W., Junn, E., Im, J., Grosso, H., Sonsalla, P. K., Feng, X., Ray, N., Fernandez, J. R., Chao, Y., et al. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.6513-10.2011 · Cited by 194
“Although -Syn-mediated microglial activation has been reported in mouse models of -Syn overexpression (Su et al., 2008; Theodore et al., 2008), it is unknown whether S129 phosphorylated -Syn is a stronger trigger of this reactive process than unphosphorylated -Syn.”
BackgroundAmyloid fibrils are the molecular trigger of inflammation in Parkinson's disease
Gustot, A., Gallea, J. I., Sarroukh, R., Celej, M. S., Ruysschaert, J., & Raussens, V. (2015) · Biochemical Journal · doi:10.1042/bj20150617 · Cited by 190
Neuropathology of multiple system atrophy: New thoughts about pathogenesis
Jellinger, K. A. (2014) · Movement Disorders · doi:10.1002/mds.26052 · Cited by 181
Immune system responses in Parkinson's disease: Early and dynamic
Tansey, M. G., & Romero‐Ramos, M. (2018) · European Journal of Neuroscience · doi:10.1111/ejn.14290 · Cited by 193
“Multiple labs have shown now that asyn can initiate a proinflammatory response in microglia inducing production of IL6, IL- 1β, and TNF (Couch, AlvarezErviti, Sibson, Wood, & Anthony, 2011; Klegeris et al., 2008; Lee et al., 2009, 2010; Roodveldt et al., 2010; Su et al., 2008).”
BackgroundInfluentialBéraud, 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
“In vitro studies confirm that α-synuclein is localized to cell membranes, released from cells including neurons (Lee et al. 2005; Su et al. 2008; Emmanouilidou et al. 2010a; Feng et al. 2010; Jang et al. 2010) and taken up by surrounding glia (Lee et al.”
BackgroundMethodInfluentialSelf-citationNeuroinflammation in Parkinson’s Disease
Lee, J., Tran, T. A. T., & Tansey, M. G. (2009) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-009-9176-0 · Cited by 174
“Evidence in support of this idea comes from studies in mice in which overexpression of wild-type α-synuclein in neurons is associated with early microglia activation, and release of α-synuclein from an αsynuclein-overexpressing DA neuron-like cell line triggers a cascade of inflammatory mediators that include TNF, IL-…”
ResultManganese promotes the aggregation and prion-like cell-to-cell exosomal transmission of α-synuclein
Harischandra, D. S., Rokad, D., Neal, M. P., Ghaisas, S., Manne, S., Sarkar, S., Panicker, N., Zenitsky, G. D., Jin, H., Lewis, M. M., et al. (2019) · Science Signaling · doi:10.1126/scisignal.aau4543 · Cited by 171
“Extracellular Syn reportedly interacts with CD36 (10), Toll-like receptor 4 (TLR4) (66) and TLR2 (67) and thus activates microglial Ctx”
BackgroundNeuroinflammation in Parkinson's disease: role in neurodegeneration and tissue repair
Vivekanantham, S., Shah, S., Dewji, R., Dewji, A., Khatri, C., & Ologunde, R. (2015) · International Journal of Neuroscience · doi:10.3109/00207454.2014.982795 · Cited by 171
“Overexpression of the wild type SYN in culture causes increased microglial expression of pro-inflammatory molecules as determined by mRNA analysis [24].”
BackgroundThe relation between α-synuclein and microglia in Parkinson’s disease: Recent developments
Sánchez-Guajardo, V., Tentillier, N., & Romero‐Ramos, M. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.02.008 · Cited by 178
The role of inflammation in sporadic and familial Parkinson’s disease
Deleidi, M., & Gasser, T. (2013) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-013-1352-y · Cited by 169
Panicker, N., Saminathan, H., Jin, H., Neal, M., Harischandra, D. S., Gordon, R., Kanthasamy, K. A., Lawana, V., Sarkar, S., Luo, J. D., et al. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.0302-15.2015 · Cited by 166
“The aggregated form of -synuclein, the primary component of PD-associated Lewy bodies, can activate microglia by using CD36- and TLR2dependent pathways (Su et al., 2008; Kim et al., 2013a).”
BackgroundNeural and Immune Mechanisms in the Pathogenesis of Parkinson’s Disease
Blandini, F. (2013) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-013-9435-y · Cited by 165
“In vivo, evidence of microglia activation is a typical finding in mice that over-express wild-type αsynuclein , along with infiltration of B and T lymphocytes in the SNc (Su et al. 2008; Theodore et al. 2008).”
BackgroundAssessment 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
“Increases in extracellular a-synuclein could trigger toxic oligomer formation and result in inflammatory glial activation [47], finally leading to neurodegeneration.”
BackgroundExtracellular Interactions of Alpha-Synuclein in Multiple System Atrophy
Valdinocci, D., Radford, R. A. W., Goulding, M., Hayashi, J., Chung, R. S., & Pountney, D. L. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19124129 · Cited by 161
Zhang, Q.-S., Heng, Y., Yuan, Y.-H., & Chen, N.-H. (2017) · Toxicology Letters · doi:10.1016/j.toxlet.2016.11.002 · Cited by 156
Glial dysfunction in the pathogenesis of α-synucleinopathies: emerging concepts
Fellner, L., Jellinger, K. A., Wenning, G. K., & Stefanova, N. (2011) · Acta Neuropathologica · doi:10.1007/s00401-011-0833-z · Cited by 162
“Enhanced dose-dependent release of pro-inflammatory molecules was reported upon a-synuclein treatment of primary microglial cells in vitro [115, 228].”
BackgroundDrouin-Ouellet, J., St-Amour, I., Saint-Pierre, M., Lamontagne-Proulx, J., Kriz, J., Barker, R. A., & Cicchetti, F. (2015) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyu103 · Cited by 153
“In particular, aggregated forms of this protein secreted by neurons of the substantia nigra (SN) could do this, leading to the production of proinflammatory mediators and thereby exacerbating neuronal death (Zhang et al., 2005; Su et al., 2008; Theodore et al., 2008; Lee et al., 2010).”
BackgroundManganese exposure induces neuroinflammation by impairing mitochondrial dynamics in astrocytes
Sarkar, S., Malovic, E., Harischandra, D. S., Ngwa, H. A., Ghosh, A., Hogan, C., Rokad, D., Zenitsky, G. D., Jin, H., Anantharam, V., et al. (2017) · NeuroToxicology · doi:10.1016/j.neuro.2017.05.009 · Cited by 151
“Furthermore, we and others have shown that aSynagg induces inflammation in microglia and astrocytes (Codolo et al., 2013; Gordon et al., 2016b; Kim et al., 2013; Su et al., 2008).”
BackgroundPark, J., Paik, S. R., Jou, I., & Park, S. M. (2008) · Glia · doi:10.1002/glia.20691 · Cited by 156
Toll-like receptors and their therapeutic potential in Parkinson’s disease and α-synucleinopathies
Kouli, A., Horne, C. B., & Williams-Gray, C. H. (2019) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2019.06.042 · Cited by 143
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
“Taken together, these data demonstrate a reduced effect of DM SYN on CD36 knock-out microglia compared to C57BL/6 microglial suggesting this scavenger receptor is in part responsible for DM SYNdependent microglial activation (Su et al. 2008).”
BackgroundMethodResultInfluentialSelf-citationAstrocytes, 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
“Alpha-synuclein also positively regulates microglia inflammatory responses and astrocyte ICAM-1 and IL-6 expression [137-139].”
BackgroundThe immune system in Parkinson's disease: what we know so far
Roodveldt, C., Bernardino, L. I., Çakmak, Ö. Ö., Dragić, M., Fladmark, K. E., Ertan, S., Aktaş, B., Pita, C., Ciglar, L., Garraux, G., et al. (2024) · Brain · doi:10.1093/brain/awae177 · Cited by 151
“The intracellular degradation of pathological α -syn leads to α -syn antigen presentation, which activates CD8 + T cells (CTLs) via class-I MHC, and CD4 + (Th and Treg) cells via class-II MHC. Th1 and Th17 T cells typically potentiate pro-inflammatory and neurotoxic events, whereas Th2 and Treg T cells support the res…”
BackgroundInfluentialPharmacological Targeting of Microglial Activation: New Therapeutic Approach
Liu, C., Wang, X., Liu, C., & Zhang, H. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00514 · Cited by 147
Sacino, A. N., Brooks, M., McKinney, A. B., Thomas, M. A., Shaw, G., Golde, T. E., & Giasson, B. I. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.2102-14.2014 · Cited by 141
“…aggregated S are potent activators of inflammation (Zhang et al., 2005; Klegeris et al., 2006, 2008; Reynolds et al., 2008; Roodveldt et al., 2008; Su et al., 2008; Lee et al., 2009; Tansey and Goldberg, 2010; Alvarez-Erviti et al., 2011; Béraud et al., 2011; Codolo et al., 2013; Fellner et al.,…”
BackgroundResultMechanisms of NLRP3 priming in inflammaging and age related diseases
Gritsenko, A., Green, J., Brough, D., & López‐Castejón, G. (2020) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2020.08.003 · Cited by 146
“Further work revealed the role of CD36 on murine microglia in regulating α -synuclein mediated microglial activation, TNF-α production and ROS generation [127].”
BackgroundGenetic mouse models of Parkinson’s disease
Magen, I., & Chesselet, M. (2010) · Progress in brain research · doi:10.1016/s0079-6123(10)84004-x · Cited by 140
Misfolded α-synuclein and toll-like receptors: therapeutic targets for Parkinson's disease
Béraud, D., & Maguire‐Zeiss, K. A. (2011) · Parkinsonism & Related Disorders · doi:10.1016/s1353-8020(11)70008-6 · Cited by 135
“An important lingering question is how does α-synuclein activate microglia? In an in vitro system utilizing microglia derived from mice devoid of the pattern recognition receptor, CD36, α-synuclein-directed activation of microglia was diminished [9].”
BackgroundSelf-citationThe 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
“…response in microglia, either evidenced through analysis of cytokine secretion (Klegeris et al., 2008; Lee et al., 2009; Béraud et al., 2013; Austin et al., 2006; Su et al., 2008; Couch et al., 2011)or reactive oxygen species (ROS) production (Thomas et al., 2007; Fellner et al., 2013).”
BackgroundHeat-Shock Proteins in Neuroinflammation
Dukay, B., Csoboz, B., & Tóth, M. E. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00920 · Cited by 139
Rab11a and HSP90 Regulate Recycling of Extracellular α-Synuclein
Liu, J., Zhang, J., Shi, M. Y., Quinn, T. J., Bradner, J. M., Beyer, R., Chen, S., & Zhang, J. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.6202-08.2009 · Cited by 136
“Furthermore, eSNCA has been shown to activate microglia (Croisier et al., 2005; Zhang et al., 2005; Su et al., 2008) and astroglia (Klegeris et al.”
BackgroundInnate and Adaptive Immunity for the Pathobiology of Parkinson's Disease
Stone, D. K., Reynolds, A. D., Mosley, R. L., & Gendelman, H. E. (2009) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.2460 · Cited by 135
“Importantly, in vivo and in vitro studies demonstrated that microglia become activated in response to overexpression of a–syn or nitrated and aggregated forms of a-syn, a major component of Lewy bodies found in the brains of PD patients (119, 130).”
BackgroundMicroglial responses to dopamine in a cell culture model of Parkinson's disease
Mastroeni, D., Grover, A., Leonard, B. W., Joyce, J. N., Coleman, P. D., Kozik, B., Bellinger, D. L., & Rogers, J. (2008) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2008.01.001 · Cited by 130
P2X7 receptor is critical in α-synuclein–mediated microglial NADPH oxidase activation
Jiang, T., Hoekstra, J., Heng, X., Kang, W., Ding, J., Liu, J., Chen, S., & Zhang, J. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.03.015 · Cited by 123
Reactive microglia enhance the transmission of exosomal α-synuclein via toll-like receptor 2
Xia, Y., Zhang, G., Kou, L., Yin, S., Han, C., Hu, J., Wan, F., Sun, Y., Wu, J., Li, Y., et al. (2021) · Brain · doi:10.1093/brain/awab122 · Cited by 123
Kim, B.-W., Koppula, S., Kumar, H., Park, J., Kim, I.-W., More, S. V., Kim, I., Han, S.-D., Kim, S., Yoon, S., et al. (2015) · Neuropharmacology · doi:10.1016/j.neuropharm.2015.04.037 · Cited by 119
“, 2003) and other neurotoxins (Choi et al., 2003; Cicchetti et al., 2002; Su et al., 2008) stimulate microglia, thereby producing proinflammatory mediators such as nitric oxide (NO), prostaglandin E2, tumor necrosis factor-alpha (TNFα), interleukin (IL)-1β and IL-6 (Cao et al.”
Metadata
- Authors
- Su, X., Maguire-Zeiss, K. A., Giuliano, R., Prifti, L., Venkatesh, K., & Federoff, H. J.
- Affiliations
- University of Rochester Medicine (US)
- Corresponding author
- Federoff, Howard J.
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2008-11
- Volume
- 29
- Issue
- 11
- Pages
- 1690-1701
- ISSN
- 0197-4580 (ISSN-L)
- PMC
- PMC2621109
- OpenAlex
- W2120997873
- Cited by
- 474
- References
- 86
- Citations by year
- 2026: 11 · 2025: 17 · 2024: 27 · 2023: 19 · 2022: 46 · 2021: 46 · 2020: 37 · 2019: 30 · 2018: 26 · 2017: 18 · 2016: 15 · 2015: 22 · 2014: 32 · 2013: 21 · 2012: 24
- FWCI
- 12.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (T32NS007489)
- 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, alpha-synuclein, microglial activation, neuroinflammation, CD36 scavenger receptor, proinflammatory molecules, Lewy bodies, MN9D cells, pathogenesis
- MeSH terms
- Animals, Cell Line, Disease Models, Animal, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Cytokines, Microglia, Parkinsonian Disorders, Mice, Synucleins
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