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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]
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Inflammatory Effects of Highly Pathogenic H5N1 Influenza Virus Infection in the CNS of Mice
Jang, H., Boltz, D. A., McClaren, J. L., Pani, A. K., Smeyne, M., Korff, A., Webster, R. G., & Smeyne, R. J. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.5123-11.2012 · Cited by 123
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Joshi, N., & Singh, S. (2017) · Journal of Neuroscience Research · doi:10.1002/jnr.24185 · Cited by 118
“Research using experimental models of PD suggests that microglial activation occurs prior to DA neuronal death, but the debate continues on this hypothesis worldwide (Castano, Herrera, Cano, & Machado, 1998; Su et al., 2008; Su, Federoff, & Maguire-Zeiss, 2009).”
MethodChapter 6 Molecular and Cellular Biology of Synucleins
Surguchov, A. P. (2008) · International review of cytology · doi:10.1016/s1937-6448(08)01406-8 · Cited by 123
“Treatment of different cell cultures with exogenous a-synuclein or overexpression of a-synuclein in MN9D cell line causes microglial activation (Su et al., 2007; Zhang et al., 2005).”
BackgroundAmyloidogenic α-synuclein seeds do not invariably induce rapid, widespread pathology in mice
Sacino, A. N., Brooks, M., Thomas, M. A., McKinney, A. B., McGarvey, N. H., Rutherford, N. J., Ceballos‐Diaz, C., Robertson, J., Golde, T. E., & Giasson, B. I. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1268-0 · Cited by 119
“However, it is also possible that other mechanisms such as the pro-inflammatory properties of αS, direct toxicity, or disrupted proteostasis could induce αS pathology [3, 7, 10, 14, 15, 17, 22, 26, 51, 53–55, 60, 64, 78, 80, 86, 87, 102].”
Backgroundα-Synuclein in Parkinson’s disease: causal or bystander?
Riederer, P. F., Berg, D., Casadei, N., Cheng, F., Claßen, J., Dresel, C., Jost, W. H., Krüger, R., Müller, T. H., Reichmann, H., et al. (2019) · Journal of Neural Transmission · doi:10.1007/s00702-019-02025-9 · Cited by 122
Etiology and Pathogenesis of Parkinson Disease
Schapira, A. H. V. (2009) · Neurologic Clinics · doi:10.1016/j.ncl.2009.04.004 · Cited by 120
Immune Response in Neurological Pathology: Emerging Role of Central and Peripheral Immune Crosstalk
Passaro, A. P., Lebos, A. L., Yao, Y., & Stice, S. L. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.676621 · Cited by 124
Cao, S., Standaert, D. G., & Harms, A. S. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-259 · Cited by 115
“independent phagocytosis has been previously reported with α-SYN [23], and can also be mediated by FcγRs through interaction with alternative ligands including complement receptors and c-reactive proteins [12-14].”
BackgroundInnate Inflammation in Parkinson's DiseasePreprint
Perry, V. H. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a009373 · Cited by 118
“The small change in TNF-a mRNA levels in vivo contrasts dramatically with the levels of TNF-a protein induced in microglia in vitro by addition of the wild-type a-synuclein protein to the cultures (Su et al. 2008), highlighting the differences between the gradual accumulation of mutant a-synuclein and the instantaneou…”
Neurodegeneration and Neuroinflammation in Parkinson’s Disease: a Self-Sustained Loop
Arena, G., Sharma, K., Agyeah, G., Krüger, R., Grünewald, A., & Fitzgerald, J. C. (2022) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-022-01207-5 · Cited by 121
Potential Modes of Intercellular α-Synuclein Transmission
Valdinocci, D., Radford, R. A. W., Siow, S. M., Chung, R. S., & Pountney, D. L. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18020469 · Cited by 114
Expression of mutant alpha-synuclein modulates microglial phenotype in vitro
Rojanathammanee, L., Murphy, E. J., & Combs, C. K. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-44 · Cited by 106
“It is assumed that microgliosis occurs during disease in part due to neuronal secretion of a-synuclein which directly stimulates microglia in a fashion requiring CD36 [16,67].”
BackgroundNuzum, N. D., Loughman, A., Szymlek-Gay, E. A., Hendy, A., Teo, W.-P., & Macpherson, H. (2020) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2020.02.003 · Cited by 103
Can Parkinson's disease pathology be propagated from one neuron to another?
Dunning, C. J. R., Reyes, J. F., Steiner, J. A., & Brundin, P. (2011) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2011.11.003 · Cited by 111
“When cell lines expressing tau with different labels were co-cultured, intracellular protein aggregates of dual colors were identified, suggesting that a transfer of fulllength tau proteins had occurred (Frost et al., 2009).”
Alpha-synuclein activates BV2 microglia dependent on its aggregation state
Hoffmann, A., Ettle, B., Bruno, A., Kulinich, A. O., Hoffmann, A.-C., von Wittgenstein, J., Winkler, J., Xiang, W., & Schlachetzki, J. C. M. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.09.109 · Cited by 111
Low‐density lipoprotein receptors regulate microglial inflammation through c‐Jun N‐terminal kinase
Pocivavsek, A., Burns, M. P., & Rebeck, G. W. (2009) · Glia · doi:10.1002/glia.20772 · Cited by 96
“Primary mouse microglial cell cultures were prepared from postnatal day 1 Swiss-Webster mouse pups using a slightly modified method from that of Su et al. (2008).”
Methodα-Synuclein pathology as a target in neurodegenerative diseases
Park, H.-J., Kam, T., Dawson, V. L., & Dawson, T. M. (2024) · Nature Reviews Neurology · doi:10.1038/s41582-024-01043-w · Cited by 121
“Pathological α-synuclein induces microglial activation 293,294 (Fig.”
DJ‐1 deficiency impairs autophagy and reduces alpha‐synuclein phagocytosis by microglia
Nash, Y., Schmukler, E., Trudler, D., Pinkas‐Kramarski, R., & Frenkel, D. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.14222 · Cited by 100
“It was previously reported that a-syn induces a proinflammatory profile shift in microglia (Zhang et al. 2005; Su et al. 2008).”
BackgroundBenskey, M. J., Sellnow, R. C., Sandoval, I. M., Sortwell, C. E., Lipton, J. W., & Manfredsson, F. P. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00036 · Cited by 102
“Supporting this theory, recombinant α-syn or conditioned media from α-syn expressing cells stimulates a pro-inflammatory response in cultured microglia (Su et al., 2008; Lee et al., 2010; Kim et al., 2016).”
BackgroundExtracellular Vesicles as Nanotherapeutics for Parkinson’s Disease
Leggio, L., Paternò, G., Vivarelli, S., L’Episcopo, F., Tirolo, C., Raciti, G., Pappalardo, F., Giachino, C., Caniglia, S., Serapide, M. F., et al. (2020) · Biomolecules · doi:10.3390/biom10091327 · Cited by 100
“production of reactive oxygen species (ROS) results in a higher oxidative stress and inflamed microenvironment for surrounding neurons [20,22,26,56,57,88,89].”
BackgroundDoorn, K. J., Goudriaan, A., Blits‐Huizinga, C. T., Bol, J. G. J. M., Rozemüller, A. J. M., Hoogland, P. V. J. M., Lucassen, P. J., Drukarch, B., van de Berg, W. D. J., & van Dam, A. (2013) · Brain Pathology · doi:10.1111/bpa.12088 · Cited by 104
“Moreover, the density of amoeboid microglial cells in the AON of PD patients did not correlate with the extent of α-syn pathology, suggesting that the increased microglial activation in this region is not proportional to the extent of α-syn deposition, but rather that a local presence of α-syn pathology is already suf…”
BackgroundRoodveldt, C., Labrador‐Garrido, A., González‐Rey, E., Fernández-Montesinos, R., Caro, M., Lachaud, C. C., Waudby, C. A., Delgado, M., Dobson, C. M., & Pozo, D. (2010) · PLoS ONE · doi:10.1371/journal.pone.0013481 · Cited by 99
“Despite the fact that some investigations in this direction have been done using monocytic cell lines [52], human astrocytes [53], or microglia [37], nothing has been reported about the cytokine expression profile of primary microglial cells induced by non-aggregated a-Syn, under conditions where the aggregation state…”
ResultImmunotherapy for Parkinson’s disease
Schwab, A. D., Thurston, M. J., Machhi, J., Olson, K. E., Namminga, K. L., Gendelman, H. E., & Mosley, R. L. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104760 · Cited by 101
Inflammation in transgenic mouse models of neurodegenerative disorders
Schwab, C., Klegeris, A., & McGeer, P. L. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2009.10.013 · Cited by 97
“[155] characterized inflammatory responses in mice expressing human wild-type Asyn under control of the rat TH promoter.”
BackgroundResultMolecular Signatures of Neuroinflammation Induced by αSynuclein Aggregates in Microglial Cells
Sarkar, S., Dammer, E. B., Malovic, E., Olsen, A. L., Raza, S. A., Gao, T., Xiao, H., Oliver, D. L., Duong, D. M., Joers, V. L., et al. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00033 · Cited by 93
“Recent studies have further shown that αSynAgg can bind to toll like receptor 2 and 4 (TLR2 and TLR4) and cluster of differentiation 36 (CD36) and thereby lead to receptor mediated activation of inflammatory signaling cascades (26, 27).”
BackgroundFcγRIIB mediates the inhibitory effect of aggregated α-synuclein on microglial phagocytosis
Choi, Y. R., Kang, S., Kim, J.-M., Lee, S., Jou, I., Joe, E.-H., & Park, S. M. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.08.025 · Cited by 88
“…has been reported to increase the production of proinflammatory cytokines and reactive oxygen species (ROS) in microglia (Klegeris et al., 2008; Su et al., 2008), causing dopaminergic neuronal death (Reynolds et al., 2008; Zhang et al., 2005), suggesting thatα-syn could actively contribute to…”
BackgroundA Spirulina-Enhanced Diet Provides Neuroprotection in an α-Synuclein Model of Parkinson's Disease
Pabon, M. M., Jernberg, J. N., Morganti, J., Contreras, J., Hudson, C. E., Klein, R. L., & Bickford, P. C. (2012) · PLoS ONE · doi:10.1371/journal.pone.0045256 · Cited by 90
“was observed [30].”
Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives
Compagnoni, G. M., & Fonzo, A. D. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0730-6 · Cited by 93
The role of natural killer cells in Parkinson’s disease
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Immune Responses in Parkinson’s Disease: Interplay between Central and Peripheral Immune Systems
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“We observe early inflammation in transgenic mice with overexpression or mutation (A53T and A30P) of α-Syn, characterized by microglial activation and increased expression in proinflammatory cytokines, prior to dopaminergic neuronal cell death andmotor disorder [16, 17].”
BackgroundInfluentialSelf-citationExperimental models of Parkinson's disease: Challenges and Opportunities
Lal, R., Singh, A., watts, S., & Chopra, K. (2024) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2024.176819 · Cited by 94
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Can we switch microglia's phenotype to foster neuroprotection? Focus on multiple sclerosis
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Induction of CNS α-synuclein pathology by fibrillar and non-amyloidogenic recombinant α-synuclein
Sacino, A. N., Brooks, M., McGarvey, N. H., McKinney, A. B., Thomas, M. A., Levites, Y., Ran, Y., Golde, T. E., & Giasson, B. I. (2013) · Acta Neuropathologica Communications · doi:10.1186/2051-5960-1-38 · Cited by 88
“These findings are consistent with cell culture studies that showed that both soluble and aggregated αS are potent activators of inflammation [49-62].”
Oligodendroglial α‐synucleinopathy‐driven neuroinflammation in multiple system atrophy
Hoffmann, A., Ettle, B., Battis, K., Reiprich, S., Schlachetzki, J. C. M., Masliah, E., Wegner, M., Kuhlmann, T., Riemenschneider, M. J., & Winkler, J. (2019) · Brain Pathology · doi:10.1111/bpa.12678 · Cited by 83
“A direct impact of α-syn on microglial activation and induction of pro-inflammatory immune responses via uptake of α-syn or binding on pathogen recognition receptors (PRRs) was observed in different in vitro as well as in vivo studies (8, 37, 82, 83, 93).”
BackgroundImmunomodulation of Parkinson’s disease using Mucuna pruriens (Mp)
Nand, S., Birla, H., Zahra, W., Singh, S. S., & Singh, S. P. (2017) · Journal of Chemical Neuroanatomy · doi:10.1016/j.jchemneu.2017.06.005 · Cited by 86
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“Furthermore, experimental data indicate that >synuclein can be taken up by microglia, and that this phagocytosis may lead to microglial activation (27, 28).”
der Perren, A. V., Macchi, F., Toelen, J., Carlon, M. S., Maris, M., de Loor, H., Kuypers, D. R. J., Gijsbers, R., den Haute, C. V., Debyser, Z., et al. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.01.014 · Cited by 87
Dendritic cells in brain diseases
Ludewig, P., Gallizioli, M., Urra, X., Behr, S., Brait, V. H., Gelderblom, M., Magnus, T. U., & Planas, A. M. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2015.11.003 · Cited by 86
Wilms, H., Rosenstiel, P. C., Romero‐Ramos, M., Arlt, A., Schäfer, H., Seegert, D., Kahle, P. J., Odoy, S., Claasen, J.-H., Holzknecht, C., et al. (2009) · International Journal of Immunopathology and Pharmacology · doi:10.1177/039463200902200405 · Cited by 84
“The exact brainderived factors controlling microglial activation in different synucleinopathies have not been identified, however there is evidence that extracellular aSyn might contribute to neuronal cell death via microglial activation (14-16).”
BackgroundShan, S., Hong-Min, T., Yi, F., Jun-Peng, G., Yue, F. L., Yan-hong, T., Yun-ke, Y., Li, W., Wang, X., Ma, J., et al. (2009) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2009.03.004 · Cited by 82
Human Interleukin-10 Gene Transfer Is Protective in a Rat Model of Parkinson's Disease
Johnston, L. C., Su, X., Maguire‐Zeiss, K. A., Horovitz, K., Ankoudinova, I., Guschin, D. Y., Hadaczek, P., Federoff, H. J., Bankiewicz, K. S., & Forsayeth, J. (2008) · Molecular Therapy · doi:10.1038/mt.2008.113 · Cited by 81
Self-citationThe role of regulatory T cells in neurodegenerative diseases
HeFeng, F. Q., & Balling, R. (2012) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.1187 · Cited by 80
Relationship Between Obesity, Alzheimer’s Disease, and Parkinson’s Disease: an Astrocentric View
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Parkinson’s disease mouse models in translational research
Antony, P. M. A., Diederich, N. J., & Balling, R. (2011) · Mammalian Genome · doi:10.1007/s00335-011-9330-x · Cited by 84
“Recently, data from tyrosine hydroxylase (TH) pro- moter-controlled a-synuclein-overexpressing mouse models led to the hypothesis that microglial activation is an early hallmark of PD (Su et al. 2008, 2009).”
BackgroundGene Therapy in Parkinsonʼs Disease
Feng, L., & Maguire‐Zeiss, K. A. (2010) · CNS Drugs · doi:10.2165/11533740-000000000-00000 · Cited by 80
Self-citationMisfolded Truncated Protein τ Induces Innate Immune Response via MAPK Pathway
Kovac, A., Zilka, N., Kazmerova, Z., Cente, M., Zilkova, M., & Novak, M. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1100216 · Cited by 75
“In particular, the class B scavenger receptor CD36 has been shown to mediate the microglial proinflammatory response to other proteins involved in neurodegeneration, amyloid b (64–66) and a-synuclein (67).”
BackgroundRole of neurotoxicants and traumatic brain injury in α-synuclein protein misfolding and aggregation
Rokad, D., Ghaisas, S., Harischandra, D. S., Jin, H., Anantharam, V., Kanthasamy, A., & Kanthasamy, A. G. (2016) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2016.12.003 · Cited by 76
“Growing in vitro evidence indicates that extracellular α-Syn induces pathogenic actions by activating neuroinflammatory and neurodegenerative responses [41, 123].”
Alpha-synuclein oligomers impair memory through glial cell activation and via Toll-like receptor 2
Vitola, P. L., Balducci, C., Cerovic, M., Santamaria, G., Brandi, E., Grandi, F., Caldinelli, L., Colombo, L., Morgese, M. G., Trabace, L., et al. (2018) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2018.02.012 · Cited by 74
The Relevance of Iron in the Pathogenesis of Multiple System Atrophy: A Viewpoint
Kaindlstorfer, C., Jellinger, K. A., Eschlböck, S., Stefanova, N., Weiß, G., & Wenning, G. K. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-170601 · Cited by 72
“Even though it is still unknown whether neuroinflammation is an initial or downstream effect [122] of synuclein and/or iron accumulation, it has been demonstrated that on the one hand, nitrated -SYN resulting from OS activates microglia [138, 199] and elevates proinflammatory mediators [200, 201] and on the other hand…”
BackgroundGenetically engineered mouse models of Parkinson's disease
Crabtree, D., & Zhang, J. (2011) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2011.07.019 · Cited by 73
“Although there was no obvious SN dopaminergic neurodegeneration, significant microglial activation was found in the brains of α-synuclein transgenic mice as young as one month [18].”
BackgroundNeuroinflammation and Glial Phenotypic Changes in Alpha-Synucleinopathies
Refolo, V., & Stefanova, N. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00263 · Cited by 72
Apoptosis Signal-Regulating Kinase 1 Mediates MPTP Toxicity and Regulates Glial Activation
Lee, K.-W., Zhao, X., Im, J., Grosso, H., Jang, W. H., Chan, T. W., Sonsalla, P. K., German, D. C., Ichijo, H., Junn, E., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0029935 · Cited by 71
“It is conceivable that a-synuclein released from dying dopamine neurons contributes to this event [33,34].”
BackgroundRusso, I., Kaganovich, A., Ding, J., Landeck, N., Mamais, A., Varanita, T., Biosa, A., Tessari, I., Bubacco, L., Greggio, E., et al. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.05.012 · Cited by 68
Feng, L., Federoff, H. J., Vicini, S., & Maguire‐Zeiss, K. A. (2010) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2010.07266.x · Cited by 72
“engineered and cultured as previously described (Luo et al., 2007; Su et al., 2008).”
MethodInfluentialSelf-citationThe Prion Hypothesis of Parkinson’s Disease
Chu, Y., & Kordower, J. H. (2015) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-015-0549-x · Cited by 74
Inflammation and neurodegeneration: the story ‘retolled’
Drouin‐Ouellet, J., & Cicchetti, F. (2012) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2012.07.002 · Cited by 71
“61 Su, X. et al. (2008) Synuclein activates microglia in a model of”
BackgroundHebron, M. L. (2014) · Journal of Clinical & Cellular Immunology · doi:10.4172/2155-9899.1000259 · Cited by 71
“Aggregated forms of αSynuclein induce microglia activation [3,4], suggesting that this may be one of the mechanisms of neurodegeneration [5,6].”
BackgroundArmentero, M., Cerri, S., & Blandini, F. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.00232 · Cited by 75
“The thy-1 a-syn transgenic model, the best characterized syn model (61), shows early and progressive increase of activated microglia specifically detected in the SN and striatum and that precedes nigrostriatal neurodegeneration (76, 77).”
BackgroundThe Role of Glia in Alpha-Synucleinopathies
Fellner, L., & Stefanova, N. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8340-3 · Cited by 69
“Cell culture models demonstrated that microglialconditioned release of pro-inflammatory cytokines upon AS treatment was dose-dependent [76,78].”
BackgroundCentral nervous system diseases related to pathological microglial phagocytosis
Wang, K., Li, J., Zhang, Y., Huang, Y., Chen, D., Shi, Z., Smith, A. D., Li, W., & Gao, Y. (2021) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.13619 · Cited by 68
Role of exosomes in the pathogenesis of inflammation in Parkinson’s disease
Yang, X., Li, K., Huang, H., & Ren, H. (2022) · Neural Regeneration Research · doi:10.4103/1673-5374.335143 · Cited by 68
“These findings suggest that α-syn can positively regulate the inflammatory responses of microglia (Su et al., 2008).”
BackgroundVekrellis, K., & Stefanis, L. (2012) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2012.674111 · Cited by 68
“There is increasing evidence suggesting that extracellularly added recombinant a-Synuclein can trigger microglial activation promoting the production of various cytokines, such as IL-1b and IL-6, and inflammation-related enzymes [82,83].”
BackgroundNanomedicine-based immunotherapy for central nervous system disorders
Hanif, S., Muhammad, P., Chesworth, R., Rehman, F. U., Qian, R., Zheng, M., & Shi, B. (2020) · Acta Pharmacologica Sinica · doi:10.1038/s41401-020-0429-z · Cited by 69
Doorn, K. J., Moors, T., Drukarch, B., van de Berg, W. D., Lucassen, P. J., & van Dam, A.-M. (2014) · Acta Neuropathologica Communications · doi:10.1186/s40478-014-0090-1 · Cited by 254
“While in vitro and experimental animal studies had demonstrated that αsynuclein can trigger microglial activation, in vivo imaging and post-mortem immunohistochemical studies have now established the presence of amoeboid microglia and proinflammatory mediators in the substantia nigra (SN) in PD [11,16-20].”
ResultPotential of cystamine and cysteamine in the treatment of neurodegenerative diseases
Gibrat, C., & Cicchetti, F. (2010) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2010.11.023 · Cited by 68
α-Synuclein in Extracellular Vesicles: Functional Implications and Diagnostic Opportunities
Lööv, C., Scherzer, C. R., Hyman, B. T., Breakefield, X. O., & Ingelsson, M. (2016) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-015-0317-0 · Cited by 68
“2015), as well as elicit neuroinflammatory reactions (Zhang et al. 2005; Su et al. 2008; Wilms et al. 2009).”
BackgroundFound in Translation: The Utility of C. elegans Alpha-Synuclein Models of Parkinson’s Disease
Gaeta, A. L., Caldwell, K. A., & Caldwell, G. A. (2019) · Brain Sciences · doi:10.3390/brainsci9040073 · Cited by 75
Cebrián, C., Loike, J. D., & Sulzer, D. (2014) · Current Topics in Behavioral Neurosciences · doi:10.1007/7854_2014_356 · Cited by 65
“Microglial activation and high levels of TNF-α were found in the SN of mice expressing human α-syn under control of the mouse TH promoter (Su et al. 2008).”
BackgroundAstroglial and microglial contributions to iron metabolism disturbance in Parkinson's disease
Song, N., Wang, J., Jiang, H. F., & Xie, J. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2018.01.008 · Cited by 63
Neuroinflammation in Parkinson’s Disease: Triggers, Mechanisms, and Immunotherapies
Wang, T., Shi, C., Luo, H., Zheng, H., Fan, L., Tang, M., Su, Y., Yang, J., Mao, C., & Xu, Y. (2021) · The Neuroscientist · doi:10.1177/1073858421991066 · Cited by 69
Caplan, I. F., & Maguire‐Zeiss, K. A. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00417 · Cited by 68
“Neurons express and release αSyn into the surrounding environment (Lee et al., 2005; Kim C. et al., 2016) and microglia recognize this with Toll-like receptors (TLRs) and subsequently produce a proinflammatory response (Zhang et al., 2005; West et al., 2006; Su et al., 2008; Vezzani et al., 2011).”
BackgroundSelf-citationBogale, T. A., Faustini, G., Longhena, F., Mitola, S. M. F., Pizzi, M., & Bellucci, A. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.611761 · Cited by 61
α‐Synuclein induces migration of BV‐2 microglial cells by up‐regulation of CD44 and MT1‐MMP
Kim, S., Cho, S., Kim, K. Y., Shin, K. Y., Kim, H., Park, C., Chang, K., Lee, S. H., Cho, D., & Suh, Y. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06075.x · Cited by 64
Fernandes, J. T. S., Chutna, O., Chu, V., Conde, J. P., & Outeiro, T. F. (2016) · Frontiers in Neuroscience · doi:10.3389/fnins.2016.00511 · Cited by 63
“Several studies have suggested that aSyn aggregation and microglia activation might be connected, resulting in chronic neuroinflammation (Streit et al., 1999; Zhang et al., 2005; Su et al., 2008).”
BackgroundInfluentialZhang, Y., Fan, J.-K., Gu, L., Yang, H., Zhan, S.-Q., & Zhang, H. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02079-1 · Cited by 61
“Extracellular α-syn secreted from neuronal cells stimulates abnormal microglia activation in many models of PD, accompanied by a large number of inflammatory factors secreted in vitro [3, 9, 10].”
BackgroundMicroglial Activation in Metal Neurotoxicity: Impact in Neurodegenerative Diseases
Martínez-Hernández, M. I., Acosta‐Saavedra, L. C., Hernández‐Kelly, L. C., Loaeza‐Loaeza, J., & Ortega, A. (2023) · BioMed Research International · doi:10.1155/2023/7389508 · Cited by 63
“Extracellular α-Syn directly activates microglia and triggers a proinflammatory phenotype [229, 230].”
Backgroundβ1-integrin-dependent migration of microglia in response to neuron-released α-synuclein
Kim, C., Cho, E.-D., Kim, H.-K., You, S., Lee, H.-J., Hwang, D., & Lee, S. (2014) · Experimental & Molecular Medicine · doi:10.1038/emm.2014.6 · Cited by 60
Alpha synuclein in hematopoiesis and immunity
Pei, Y., & Maitta, R. W. (2019) · Heliyon · doi:10.1016/j.heliyon.2019.e02590 · Cited by 62
Anandhan, A., Nguyen, N., Syal, A., Dreher, L. A., Dodson, M. B., Zhang, D. D., & Madhavan, L. (2021) · Aging and Disease · doi:10.14336/ad.2021.0511 · Cited by 59
“α-Syn, which is a major constituent of Lewy bodies, has been shown to bind to and activate microglia through toll-like receptors (TLRs) that mediate innate immunity [30, 51, 52].”
BackgroundConant, K. E., Lonskaya, I., Szklarczyk, A., Krall, C., Steiner, J. P., Maguire‐Zeiss, K. A., & Seung Taik, L. I. M. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.07153.x · Cited by 58
“These cells have previously been shown to express dopamine receptors and transporters (Su et al. 2008).”
BackgroundSelf-citationCao, B., Zhang, Y., Chen, J., Wu, P., Dong, Y., & Wang, Y. (2021) · Metabolic Brain Disease · doi:10.1007/s11011-021-00879-1 · Cited by 57
“In various animal PD models, this neuroinflammation is also accompanied by the activation of substantia nigra glial in the midbrain (McGeer and McGeer 2008; Na et al. 2010; Su et al. 2008).”
BackgroundPonce, J., Ulu, A., Hanson, C., Cameron‐Smith, E., Bertoni, J. M., Wuebker, J., Fisher, A. L., Siu, K., Marmelat, V., Adamec, J., et al. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.780811 · Cited by 59
Multifunctional role of natural products for the treatment of Parkinson’s disease: At a glance
Rahman, M. M., Wang, X., Islam, M. R., Akash, S., Supti, F. A., Mitu, M. I., Harun-Or-Rashid, M., Aktar, M. N., Kali, M. S. K., Jahan, F. I., et al. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.976385 · Cited by 60
Prasanth, M. I., Sivamaruthi, B. S., Cheong, C. S. Y., Verma, K., Tencomnao, T., Brimson, J. M., & Prasansuklab, A. (2024) · Antioxidants · doi:10.3390/antiox13050606 · Cited by 65
“Reports show that α -synuclein can instigate inflammatory response, causing further neuronal loss [158,159].”
BackgroundCD36 in the periphery and brain synergizes in stroke injury in hyperlipidemia
Kim, E., Febbraio, M., Bao, Y., Tolhurst, A. T., Epstein, J. M., & Cho, S. (2012) · Annals of Neurology · doi:10.1002/ana.23569 · Cited by 58
Microglia as therapeutic target in central nervous system disorders
Fatoba, O., Itokazu, T., & Yamashita, T. (2020) · Journal of Pharmacological Sciences · doi:10.1016/j.jphs.2020.07.004 · Cited by 57
Microglial Extracellular Vesicles as Vehicles for Neurodegeneration Spreading
Aires, I. D., Ribeiro‐Rodrigues, T., Boia, R., Ferreira-Rodrigues, M., Girão, H., Ambrósio, A. F., & Santiago, A. R. (2021) · Biomolecules · doi:10.3390/biom11060770 · Cited by 57
“It was demonstrated that α-synuclein triggers microglial activation [27,28] and in vivo imaging and post-mortem immunohistochemical studies revealed the presence of activated microglia in the substantia nigra of PD patients [29–32].”
BackgroundTapias, V., McCoy, J. L., & Greenamyre, J. T. (2019) · Redox Biology · doi:10.1016/j.redox.2019.101164 · Cited by 57
Protective mechanism of Syringic acid in an experimental model of Parkinson’s disease
Güzelad, Ö., Özkan, A., Parlak, H., Sinen, O., Afşar, E., Öğüt, E., Yıldırım, F. B., Bülbül, M., Ağar, A., & Aslan, M. (2021) · Metabolic Brain Disease · doi:10.1007/s11011-021-00704-9 · Cited by 55
Protein Transmission, Seeding and Degradation: Key Steps for α-Synuclein Prion-Like Propagation
Oueslati, A., Ximerakis, M., & Vekrellis, K. (2014) · Experimental Neurobiology · doi:10.5607/en.2014.23.4.324 · Cited by 58
“In support of this, a growing number of reports have demonstrated that various species of α-syn when applied extracellularly are potent to induce multiple neurotoxic [9, 11, 17] and inflammatory responses [18-24], as well as, to cause deleterious seeding effects [25].”
BackgroundLindström, V., Ihse, E., Fagerqvist, T., Bergström, J. J. E., Nordström, E. K. L., Möller, C., Lannfelt, L., & Ingelsson, M. (2014) · Immunotherapy · doi:10.2217/imt.13.162 · Cited by 56
Bang, S., Lee, S., Choi, N., & Kim, H. N. (2021) · Advanced Healthcare Materials · doi:10.1002/adhm.202002119 · Cited by 57
Astrocytes and endoplasmic reticulum stress: A bridge between obesity and neurodegenerative diseases
Martín-Jiménez, C., García-Vega, Á. S., Cabezas, R., Aliev, G., Echeverrı́a, V., González, J., & Barreto, G. E. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.08.001 · Cited by 56
“In ways similar to ATF6 during UPR activation, OASIS is translocated to the Golgi apparatus and suffers a protein cleavage with the resulting Nterminal protein promoting the transcription of ERAD elements in astrocytes (Kondo et al., 2005; Su et al., 2008).”
BackgroundActivated microglia facilitate the transmission of α-synuclein in Parkinson's disease
Zheng, T., & Zhang, Z. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.105094 · Cited by 57
Zhao, N., Yang, X., Calvelli, H. R., Cao, Y., Francis, N. L., Chmielowski, R., Joseph, L. B., Pang, Z. P., Uhrich, K. E., Baum, J., et al. (2020) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2020.00112 · Cited by 54
Identification of the amino acid sequence motif of α-synuclein responsible for macrophage activation
Lee, S.-B., Park, S. M., Ahn, K. J., Chung, K. C., Paik, S. R., & Kim, J. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.02.002 · Cited by 52
“In particular, the ERK pathway is activated by a-synuclein treatment in microglia and astrocytes [15,16].”
Potential Future Neuroprotective Therapies for Neurodegenerative Disorders and Stroke
Tarawneh, R. M., & Galvin, J. E. (2010) · Clinics in Geriatric Medicine · doi:10.1016/j.cger.2009.12.003 · Cited by 54
Uriarte Huarte, O., Kyriakis, D., Heurtaux, T., Pires-Afonso, Y., Grzyb, K., Halder, R., Buttini, M., Skupin, A., Mittelbronn, M., & Michelucci, A. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.639613 · Cited by 52
“Microglia actively contribute to PD pathology by reacting to a-syn (49).”
BackgroundNeurons and Glia Interplay in α-Synucleinopathies
Mavroeidi, P., & Xilouri, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094994 · Cited by 55
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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