Neuroinflammation and α-Synuclein Dysfunction Potentiate Each Other, Driving Chronic Progression of Neurodegeneration in a Mouse Model of Parkinson’s Disease
Open accessAbstract
Background: Mechanisms whereby gene–environment interactions mediate chronic, progressive neurodegenerative processes in Parkinson’s disease (PD)—the second most common neurodegenerative disease—remain elusive. Objective: We created a two-hit [neuroinflammation and mutant α-synuclein (α-syn) overexpression] animal model to investigate mechanisms through which mutant α-syn and inflammation work in concert to mediate chronic PD neurodegeneration. Methods: We used an intraperitoneal injection of the inflammogen lipopolysaccharide (LPS; 3 × 106 EU/kg) to initiate systemic and brain inflammation in wild-type (WT) mice and transgenic (Tg) mice overexpressing human A53T mutant α-syn. We then evaluated nigral dopaminergic neurodegeneration, α-syn pathology, and neuroinflammation. Results: After LPS injection, both WT and Tg mice initially displayed indistinguishable acute neuroinflammation; however, only Tg mice developed persistent neuroinflammation, chronic progressive degeneration of the nigrostriatal dopamine pathway, accumulation of aggregated, nitrated α-syn, and formation of Lewy body-like inclusions in nigral neurons. Further mechanistic studies indicated that 4-week infusion of two inhibitors of inducible nitric oxide synthase and NADPH oxidase, major free radical–generating enzymes in activated microglia, blocked nigral α-syn pathology and neurodegeneration in LPS-injected Tg mice. Conclusions: Microglia-derived oxidative stress bridged neuroinflammation and α-syn pathogenic alteration in mediating chronic PD progression. Our two-hit animal model involving both a genetic lesion and an environmental trigger reproduced key features of PD and demonstrated synergistic effects of genetic predisposition and environmental exposures in the development of PD. The chronic progressive nature of dopaminergic neurodegeneration, which is absent in most existing PD models, makes this new model invaluable for the study of mechanisms of PD progression.
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Chronic neuroinflammation has been shown to increase α-synuclein deposition in various synucleinopathy animal models.
“Not only has chronic neuroinflammation been shown to increase α-synuclein deposition in various synucleinopathy animal models (51–56), but when these animals were treated with drugs to reduce neuroinflammation, α-synuclein neuropathology also decreased (57, 58).”
From LRRK2 mediates microglial neurotoxicity via NFATc2 in rodent models of synucleinopathies (2020) · cites this paper as [53]
This supports a dual-hit hypothesis for Parkinson's disease: elevated endotoxin plus aggregable α-synuclein results in neurodegeneration.
“This supports a dual-hit hypothesis for PD: elevated endotoxin plus aggregable α-synuclein results in neurodegeneration.”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [101]
A single injection of peripheral endotoxin into wild-type mice and transgenic mice expressing human A53T mutant α-synuclein resulted in indistinguishable acute neuroinflammation, but only the transgenic mice treated with endotoxin developed persistent neuroinflammation, aggregated α-synuclein, progressive degeneration of dopamine neurons and Lewy body-like inclusions in nigral neurons.
“A single injection of peripheral endotoxin into wild-type mice and transgenic mice (expressing human A53T mutant α-synuclein) resulted in indistinguishable acute neuroinflammation, but only the transgenic mice treated with endotoxin developed persistent neuroinflammation, aggregated α-synuclein, progressive degeneration of dopamine neurons and Lewy body-like inclusions in nigral neurons [101].”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [101]
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“Intriguingly, aSyn aggregation can be enhanced by an inflammatory environment, which may further activate microglia upon contact and promote a feed-forward cascade that leads to additional aSyn aggregation and propagation and progression of PD (Gao et al. 2011).”
BackgroundMicroglia Phenotypes in Aging and Neurodegenerative Diseases
Wendimu, M. Y., & Hooks, S. B. (2022) · Cells · doi:10.3390/cells11132091 · Cited by 336 · see citing works
Uemura, N., Yagi, H., Uemura, M. T., Hatanaka, Y., Yamakado, H., & Takahashi, R. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0257-5 · Cited by 328 · see citing works
Pathogenesis of Parkinson's disease
Hirsch, E. C., Jenner, P., & Przedborski, S. (2013) · Movement Disorders · doi:10.1002/mds.25032 · Cited by 336 · see citing works
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Villumsen, M., Aznar, S., Pakkenberg, B., Jess, T., & Brudek, T. (2018) · Gut · doi:10.1136/gutjnl-2017-315666 · Cited by 315 · see citing works
Williams‐Gray, C. H., Wijeyekoon, R., Yarnall, A. J., Lawson, R. A., Breen, D. P., Evans, J., Cummins, G. A., Duncan, G. W., Khoo, T. K., Burn, D. J., et al. (2016) · Movement Disorders · doi:10.1002/mds.26563 · Cited by 311 · see citing works
Microglial phenotypes in Parkinson’s disease and animal models of the disease
Joers, V., Tansey, M. G., Mulas, G., & Carta, A. R. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2016.04.006 · Cited by 285 · see citing works
“…have provided positive results in preclinical models; however epidemiological studies have yielded conflicting results on the extent to which chronic intake of these drugs reduce the risk of PD (Bower et al., 2006; Chen et al., 2005; Esposito et al., 2007; Gao et al., 2011b; Noyce et al., 2012).”
BackgroundResultNeuroinflammation 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
“In support of a further link between -syn and a neuroinflammatory response, IP injection of LPS into human A53T mice led to a persistent neuroinflammatory response compared to wildtype mice (Gao et al., 2011).”
BackgroundInflammatory dysregulation of blood monocytes in Parkinson’s disease patients
Grozdanov, V., Bliederhaeuser, C., Ruf, W. P., Roth, V., Fundel-Clemens, K., Zondler, L., Brenner, D., Martin-Villalba, A., Hengerer, B., Kassubek, J., et al. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1345-4 · Cited by 295 · see citing works
“[22], who showed that LPS-induced inflammation and alpha-synuclein pathology act synergistically and potentiate neurodegeneration in a genetic mouse model of PD.”
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 279 · see citing works
Wang, W., Nguyen, L. T. T., Burlak, C., Chegini, F., Guo, F., Chataway, T., Ju, S., Fisher, O. S., Miller, D. W., Datta, D., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1610099113 · Cited by 270 · see citing works
Interplay of endoplasmic reticulum stress and autophagy in neurodegenerative disorders
Cai, Y. C., Arikkath, J., Yang, L., Guo, M., Periyasamy, P., & Buch, S. J. (2016) · Autophagy · doi:10.1080/15548627.2015.1121360 · Cited by 258 · see citing works
Urrutia, P. J., Mena, N. P., & NÃoñez, M. T. (2014) · Frontiers in Pharmacology · doi:10.3389/fphar.2014.00038 · Cited by 243 · see citing works
“Debris and toxins from dying neurons enhance the activation of glial cells, which contributes to the inflammatory network (Zecca et al., 2008; Hirsch and Hunot,2009; Gao et al., 2011) [12].”
BackgroundInflammation and α-Synuclein’s Prion-like Behavior in Parkinson's Disease—Is There a Link?
Tomé, C. M. L., Tyson, T., Rey, N. L., Grathwohl, S. A., Britschgi, M., & Brundin, P. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8267-8 · Cited by 237 · see citing works
“Factors released from activated microglia can further enhance oxidative stress, protein misfolding, and aggregation, creating a positive feedback loop promoting degeneration of dopaminergic cells [46, 47].”
BackgroundSánchez-Guajardo, V., Barnum, C. J., Tansey, M. G., & Romero‐Ramos, M. (2013) · ASN NEURO · doi:10.1042/an20120066 · Cited by 237 · see citing works
“These animals developed persistent inflammation, and via free radicals, likely from activated microglia, induced nitration and aggregation of α-syn, resulting in DA neuron degeneration (Gao et al., 2011).”
BackgroundJang, J., Yeom, M., Ahn, S., Oh, J., Ji, S., Kim, T., & Park, H. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.08.015 · Cited by 232 · see citing works
“An inflammatory environment can enhance αsynuclein aggregation, which further activates microglia upon contact and promote a feed-forward cascade that leads to additional α-synuclein aggregation and propagation, and progression of disease (Gao et al., 2011).”
BackgroundMicroglia affect α-synuclein cell-to-cell transfer in a mouse model of Parkinson’s disease
George, S., Rey, N. L., Tyson, T., Esquibel, C., Meyerdirk, L., Schulz, E., Pierce, S., Burmeister, A. R., Madaj, Z., Steiner, J. A., et al. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0335-3 · Cited by 229 · see citing works
microRNAs in Parkinson’s Disease: From Pathogenesis to Novel Diagnostic and Therapeutic Approaches
Leggio, L., Vivarelli, S., L’Episcopo, F., Tirolo, C., Caniglia, S., Testa, N., Marchetti, B., & Iraci, N. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18122698 · Cited by 216 · see citing works
“As previously introduced, neuroinflammation is a major hallmark of PD [11,25,28] and high levels of proinflammatory cytokines IL-1β, TNF-α, IL-6 and INF-γ, are produced in PD brains, as well as in MPTP-treated mouse models [107].”
BackgroundNADPH oxidases: novel therapeutic targets for neurodegenerative diseases
Gao, H., Zhou, H., & Hong, J. (2012) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2012.03.008 · Cited by 212 · see citing works
Self-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 199 · see citing works
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 198 · see citing works
“A transgenic mouse (overexpressing human A53T mutation) exposed to LPS revealed an increase in neuroinflammation, protein aggregation, DAn loss, and Lewy body (LBs) formation in the nigrostriatal neurons compared to wild-type animals [230].”
BackgroundInfluentialLipid nanoparticle-mediated drug delivery to the brain
Khare, P., Edgecomb, S. X., Hamadani, C. M., Tanner, E. E. L., & S Manickam, D. (2023) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2023.114861 · Cited by 187 · see citing works
Microglial Phagocytosis and Its Regulation: A Therapeutic Target in Parkinson’s Disease?
Janda, E., Boi, L., & Carta, A. R. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00144 · Cited by 175 · see citing works
“Transgenic mice overexpressing human A53T α -SYN develop chronic neuroinflammation and progressive degeneration together with microglia-derived oxidative stress (Gao et al., 2011).”
Marchetti, B., Tirolo, C., L’Episcopo, F., Caniglia, S., Testa, N., Smith, J. A., Pluchino, S., & Serapide, M. F. (2020) · Aging Cell · doi:10.1111/acel.13101 · Cited by 185 · see citing works
“In PD especially, glial inflammatory mechanisms have long been recognized to contribute to both nigrostriatal degeneration and self-repair (see Gao et al., 2011; Hirsh & Hunot, 2009; L'Episcopo, Tirolo, PeruzzottiJametti, et al., 2018a; L'Episcopo, Tirolo, Serapide, et al., 2018b; Marchetti &…”
BackgroundImmune 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 183 · see citing works
“A single peripheral injection of LPS in a- syn transgenic mice resulted in persistent inflammation, increase oxidative stress, which induced nitration and aggregation of a- syn resulting in dopaminergic neurodegeneration (Gao et al., 2011a).”
BackgroundAntioxidant gene therapy against neuronal cell death
Navarro-Yepes, J., Zavala-Flores, L. M., Anandhan, A., Wang, F., Skotak, M., Chandra, N., Li, M., Pappa, A., Martínez‐Fong, D., Razo, L. M. D., et al. (2013) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.12.007 · Cited by 177 · see citing works
“Epidemiological evidence shows an increase in the risk of developing PD upon the exposure to environmental toxicants such as pesticides, metals, polychlorinated biphenyls, as well as early life inflammatory processes (Gao et al., 2011a).”
The immunomodulatory mechanisms for acupuncture practice
Wang, M., Liu, W., Ge, J., & Liu, S.-B. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1147718 · Cited by 186 · see citing works
Manganese 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 170 · see citing works
“These results support recent observations indicating that neuroinflammation plays a major role in PD (36).”
Neuroinflammation 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 · see citing works
Kenk, M., Selvanathan, T., Rao, N. P., Suridjan, I., Rusjan, P., Remington, G. J., Meyer, J. H., Wilson, A. A., Houle, S., & Mizrahi, R. (2014) · Schizophrenia Bulletin · doi:10.1093/schbul/sbu157 · Cited by 169 · see citing works
Lewy body-like alpha-synuclein inclusions trigger reactive microgliosis prior to nigral degeneration
Duffy, M. F., Collier, T. J., Patterson, J. R., Kemp, C. J., Luk, K. C., Tansey, M. G., Paumier, K. L., Kanaan, N. M., Fischer, D. L., Polinski, N. K., et al. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1171-z · Cited by 197 · see citing works
Gene–environment interactions: Key to unraveling the mystery of Parkinson's disease
Gao, H., & Hong, J. (2011) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2011.03.005 · Cited by 164 · see citing works
Self-citationAnandhan, A., Jacome, M. S., Lei, S., Hernández-Franco, P., Pappa, A., Panayiotidis, M. I., Powers, R., & Franco, R. (2017) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2017.03.009 · Cited by 161 · see citing works
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 · see citing works
Boyd, R. J., Avramopoulos, D., Jantzie, L. L., & McCallion, A. S. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02584-x · Cited by 162 · see citing works
“Many PD mutations are now believed to elicit this response through pathways involving oxidative stress [148], and numerous pan-ethnic PD risk loci (i.”
BackgroundCouch, Y., Alvarez-Erviti, L., Sibson, N. R., Wood, M. J., & Anthony, D. C. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-166 · Cited by 155 · see citing works
“Recent work by Gao and colleagues has substantiated this finding by using a two-hit approach, systemic inflammation in a transgenic model of PD [36].”
ResultThe NLRP3 Inflammasome is Involved in the Pathogenesis of Parkinson’s Disease in Rats
Mao, Z., Liu, C., Ji, S., Yang, Q., Ye, H., Han, H., & Xue, Z. (2017) · Neurochemical Research · doi:10.1007/s11064-017-2185-0 · Cited by 155 · see citing works
Parkinson’s disease and enhanced inflammatory response
Stojkovska, I., Wagner, B. M., & Morrison, B. E. (2015) · Experimental Biology and Medicine · doi:10.1177/1535370215576313 · Cited by 146 · see citing works
Redox Mechanisms in Neurodegeneration: From Disease Outcomes to Therapeutic Opportunities
Sbodio, J. I., Snyder, S. H., & Paul, B. D. (2018) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7321 · Cited by 143 · see citing works
Konno, T., Melo, E. P., Chambers, J. E., & Avezov, E. (2021) · Cells · doi:10.3390/cells10020233 · Cited by 140 · see citing works
Ortega, R. H., Cerezo, A. B., de Pablos, R. M., Krisa, S., Richard, T., García-Parrilla, M. C., & Troncoso, A. M. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00373 · Cited by 130 · see citing works
Air Pollution and the Risk of Parkinson's Disease: A Review
Murata, H., Barnhill, L. M., & Bronstein, J. M. (2022) · Movement Disorders · doi:10.1002/mds.28922 · Cited by 126 · see citing works
“There is strong evidence in animal models that systemic inflammation can lead to neuroinflammation and loss of dopaminergic neurons, especially in combinationwith elevated α-syn levels.(72) Taken together, air pollution induces a systemic inflammatory response that may lead to neuroinflammation and an elevated risk fo…”
BackgroundThinking laterally about neurodegenerative proteinopathies
Golde, T. E., Borchelt, D., Giasson, B. I., & Lewis, J. M. (2013) · Journal of Clinical Investigation · doi:10.1172/jci66029 · Cited by 121 · see citing works
Kiely, A. P., Ling, H., Asi, Y. T., Kara, E., Proukakis, C., Schapira, A. H. V., Morris, H. R., Roberts, H. C., Lubbe, S. J., Limousin, P. D., et al. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0038-3 · Cited by 124 · see citing works
“In general the insight gained from investigations into in vitro disease models has been limited as they do not account for the contribution of factors such as dysfunction of clearance mechanisms [48] and neuroinflammation [49, 50] as in the disease state.”
BackgroundHall, D. A., Voigt, R. M., Cantu-Jungles, T. M., Hamaker, B., Engen, P. A., Shaikh, M., Raeisi, S., Green, S. J., Naqib, A., Forsyth, C. B., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-36497-x · Cited by 124 · see citing works
Amyloidogenic 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 115 · see citing works
“Indeed, exogenous stressors such as lipopolysaccharide can trigger αS pathology in the M83 Tg mouse line [28, 29], and there is growing evidence that exogenous amyloidogenic proteins like αS, especially when aggregated, act as danger associated molecular patterns to activate innate immunity [38, 81].”
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 118 · see citing works
New Perspectives on Roles of Alpha-Synuclein in Parkinson’s Disease
Zhang, G., Xia, Y. F., Wan, F. J., Ma, K., Guo, X., Kou, L., Yin, S., Han, C., Liu, L., Huang, J., et al. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00370 · Cited by 115 · see citing works
“…species can trigger activation of glia (Beraud et al., 2011), one of the hallmarks of the neuroinflammatory process, from which released factors could create oxidative stress, enhance protein misfolding, and promote further inflammation and degeneration of dopaminergic cells (Gao et al., 2011).”
BackgroundGut Vibes in Parkinson's Disease: The Microbiota‐Gut‐Brain Axis
Bullich‐Vilarrubias, C., Keshavarzian, A., Garssen, J., Kraneveld, A. D., & Perez‐Pardo, P. (2019) · Movement Disorders Clinical Practice · doi:10.1002/mdc3.12840 · Cited by 116 · see citing works
“αSyn-induced microglia activation would, in turn, potentiate further αSyn aggregation and propagation specifically in nigrostriatal dopaminergic neurodegeneration, thus contributing to PD progression.(27,49) Another possible mechanism for the GM to induce oxidative stress and neuroinflammation is through gut-derived m…”
BackgroundDeng, I. B., Corrigan, F., Zhai, G., Zhou, X., & Bobrovskaya, L. (2020) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2020.100060 · Cited by 120 · see citing works
Kishimoto, Y., Zhu, W. S., Hosoda, W., Sen, J. M., & Mattson, M. P. (2019) · NeuroMolecular Medicine · doi:10.1007/s12017-019-08539-5 · Cited by 115 · see citing works
Neuroinflammation in Neurodegenerative Disorders: Current Knowledge and Therapeutic Implications
Giri, P. M., Banerjee, A., Ghosal, A., & Layek, B. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25073995 · Cited by 123 · see citing works
“Furthermore, Gao et al. [110] demonstrated that oxidative stress caused by microglia is linked to neuroinflammation and α-synuclein pathogenesis in chronic PD progression.”
BackgroundInnate Inflammation in Parkinson's DiseasePreprint
Perry, V. H. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a009373 · Cited by 113 · see citing works
Tentillier, N., Etzerodt, A., Olesen, M. N., Rizalar, F. S., Jacobsen, J., Bender, D., Moestrup, S. K., & Romero-Ramos, M. (2016) · The Journal of Neuroscience · doi:10.1523/jneurosci.1636-16.2016 · Cited by 109 · see citing works
“Further supporting a role of peripheral cells, unrelated inflammatory peripheral events increase neurodegeneration in PD models (Villaran et al., 2010; Gao et al., 2011).”
BackgroundParkin regulates microglial NLRP3 and represses neurodegeneration in Parkinson's disease
Yan, Y., Zheng, R., Liu, Y., Ruan, Y., Lin, Z., Xue, N., Chen, Y., Zhang, B., & Pu, J. (2023) · Aging Cell · doi:10.1111/acel.13834 · Cited by 110 · see citing works
“These results support the two- hit theory of PD pathogenesis, which involves synergy between gene mutations and environmental stress, and may support the gut- brain axis theory (Avagliano et al., 2022; Gao et al., 2011).”
ResultKoppula, S., Kumar, H., Kim, I. S., & Choi, D. (2012) · Mediators of Inflammation · doi:10.1155/2012/823902 · Cited by 107 · see citing works
“[76] developed a two-hit (neuroinflammation and mutant α-synuclein (αsyn) overexpression) animal model to investigate mechanisms through which mutant α-syn and inflammation work in concert to mediate chronic PD neurodegeneration.”
BackgroundWijeyekoon, R., Kronenberg‐Versteeg, D., Scott, K. M., Hayat, S., Kuan, W., Evans, J., Breen, D. P., Cummins, G. A., Jones, J., Clatworthy, M. R., et al. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.01.018 · Cited by 102 · see citing works
Arneth, B. M. (2018) · Postgraduate Medical Journal · doi:10.1136/postgradmedj-2017-135424 · Cited by 104 · see citing works
Wang, Q., Li, Q., Chen, S., Chu, C., Wilson, B. C., Oyarzabal, E. A., Ali, S. F., Robinson, B. L., Rao, D. B., & Hong, J. (2015) · Brain · doi:10.1093/brain/awv034 · Cited by 103 · see citing works
Self-citationEpigenomic analysis of Parkinson’s disease neurons identifies Tet2 loss as neuroprotective
Marshall, L. L., Killinger, B. A., Ensink, E., Li, P., Li, K. X., Cui, W., Lubben, N., Weiland, M. J., Wang, X., Gordevičius, J., et al. (2020) · Nature Neuroscience · doi:10.1038/s41593-020-0690-y · Cited by 97 · see citing works
Abnormalities of age-related T cell senescence in Parkinson’s disease
Williams‐Gray, C. H., Wijeyekoon, R., Scott, K. M., Hayat, S., Barker, R., & Jones, J. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1206-5 · Cited by 98 · see citing works
Main, B. S., Zhang, M., Brody, K. M., Ayton, S., Frugier, T., Steer, D., Finkelstein, D., Crack, P. J., & Taylor, J. M. (2016) · Glia · doi:10.1002/glia.23028 · Cited by 92 · see citing works
“…and genetic analysis is required to determine if the type-1 IFNs correlate with disease severity, or potentially a particular genetic mutation such as LRRK2 (Gillardon et al., 2012; Kim et al., 2012; Moehle et al., 2012) or a-synuclein (Gao et al., 2011; Roodveldt et al., 2008; Zhang et al., 2005).”
BackgroundGenetic variants and animal models in SNCA and Parkinson disease
Deng, H., & Yuan, L. (2014) · Ageing Research Reviews · doi:10.1016/j.arr.2014.04.002 · Cited by 89 · see citing works
Immune Responses in Parkinson’s Disease: Interplay between Central and Peripheral Immune Systems
Su, X., & Federoff, H. J. (2014) · BioMed Research International · doi:10.1155/2014/275178 · Cited by 91 · see citing works
Peripheral inflammation exacerbates α‐synuclein toxicity and neuropathology in Parkinson's models
Vitola, P. L., Balducci, C., Baroni, M., Artioli, L., Santamaria, G., Castiglioni, M., Cerovic, M., Colombo, L., Caldinelli, L., Pollegioni, L., et al. (2020) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12644 · Cited by 89 · see citing works
Huang, B., Liu, J., Ju, C., Yang, D., Chen, G., Xu, S. S., Zeng, Y., Yan, X., Wang, W., Liu, D., et al. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18102043 · Cited by 86 · see citing works
“It is widely recognized that multiple immunological stimuli such as α-synuclein, TNF-α and LPS can trigger microglial activation, leading to sustained chronic inflammation in the dopaminergic neurodegenerative process [10,20].”
BackgroundNeuroinflammation and Its Impact on the Pathogenesis of COVID-19
Almutairi, M. M., Sivandzade, F., Albekairi, T. H., Alqahtani, F., & Cucullo, L. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.745789 · Cited by 88 · see citing works
“Excessive neuroinflammation contributes to neuronal death and neurodegenerative diseases (111, 186).”
BackgroundOxidative Stress in Genetic Mouse Models of Parkinson’s Disease
Varçin, M., Bentea, E., Michotte, Y. M., & Sarre, S. (2012) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2012/624925 · Cited by 84 · see citing works
“In addition, a treatment with two inhibitors of inducible NOS and NADPH oxidase blocked the neurodegeneration in LPS-injected transgenic mice [156].”
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 86 · see citing works
“For example, there are extensive reports on how extracellular αS can lead to activation of the innate immune response via toll-like receptor pathways akin to lipopolysaccharide activation [49-62], and single intracerebellar or intraperitoneal injections of lipopolysaccharide have been shown to result in the long-lasti…”
Okuzumi, A., Kurosawa, M., Hatano, T., Takanashi, M., Shuuko, N., Fukuhara, T., Yamanaka, T., Miyazaki, H., Yoshinaga, S., Furukawa, Y., et al. (2018) · Acta Neuropathologica Communications · doi:10.1186/s40478-018-0587-0 · Cited by 87 · see citing works
Bassoon proteinopathy drives neurodegeneration in multiple sclerosis
Schattling, B., Engler, J. B., Volkmann, C., Rothammer, N., Woo, M. S., Petersen, M., Winkler, I., Kaufmann, M., Rosenkranz, S. C., Fejtová, A., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0385-4 · Cited by 83 · see citing works
L’Episcopo, F., Tirolo, C., Serapide, M. F., Caniglia, S., Testa, N., Leggio, L., Vivarelli, S., Iraci, N., Pluchino, S., & Marchetti, B. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00012 · Cited by 84 · see citing works
“…stress and inflammation, contributing to the chronic PD progression (Di Monte et al., 2002; Marchetti and Abbracchio, 2005; Zhang et al., 2005; Whitton, 2007, 2010; Gao and Hong, 2008, 2011; Przedborski, 2010; Tansey and Goldberg, 2010; Gao et al., 2011, 2012; Lastres-Becker et al., 2012; Table 1).”
BackgroundInfluentialWang, Q., Chu, C., Li, Q., Chen, S., Wilson, B. C., Oyarzabal, E. A., Jiang, L., Ali, S. F., Robinson, B. L., Kim, H., et al. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.2238-14.2014 · Cited by 84 · see citing works
“Previous studies have demonstrated consistency of dopaminergic neuron quantitation by counting THir and NeuN/Nisslimmunoreactive cells in the SNpc of PD models (Gao et al., 2011a; Baiguera et al., 2012; Tonges et al., 2012).”
ResultSelf-citationder 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 83 · see citing works
“Microglia activation and neuroinflammation have been described in various a-synuclein models, but the therapeutic relevance has not yet been demonstrated (Gao et al., 2011; Su et al., 2008, 2009; Theodore et al., 2008).”
BackgroundBeyond α-synuclein transfer: pathology propagation in Parkinson's disease
Hansen, C., & Li, J. (2012) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2012.03.002 · Cited by 82 · see citing works
Latchoumycandane, C., Anantharam, V., Jin, H., Kanthasamy, A. G., & Kanthasamy, A. (2011) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2011.07.021 · Cited by 82 · see citing works
“…animal models (Moore et al., 2005; Andrabi et al., 2008; Henchcliffe and Beal, 2008; Zhou et al., 2008; Lee et al., 2009; Naoi et al., 2009; Shin et al., 2009; Tsang and Chung, 2009; Beal, 2010; Cannon and Greenamyre, 2010; Horowitz and Greenamyre, 2010; Kanthasamy et al., 2010; Gao et al., 2011).”
BackgroundThundyil, J., & Lim, K. (2014) · Ageing Research Reviews · doi:10.1016/j.arr.2014.11.003 · Cited by 82 · see citing works
Bae, E.-J., Choi, M.-S., Kim, J. T., Kim, D., Jung, M. K., Kim, C., Kim, T.-K., Lee, J. S., Jung, B. C., Shin, S. J., et al. (2022) · Experimental & Molecular Medicine · doi:10.1038/s12276-022-00789-x · Cited by 81 · see citing works
Lim, J., Bang, Y., & Choi, H. J. (2018) · Archives of Pharmacal Research · doi:10.1007/s12272-018-1063-x · Cited by 80 · see citing works
The Endotoxin Hypothesis of Parkinson's Disease
Brown, G. C., Camacho, M., & Williams‐Gray, C. H. (2023) · Movement Disorders · doi:10.1002/mds.29432 · Cited by 81 · see citing works
“Peripheral injection of endotoxin into control mice and A53T α-synuclein transgenic mice caused similar acute neuroinflammation, but only the transgenic mice then developed persistent neuroinflammation, α-synuclein aggregation, Lewy bodies, and progressive loss of dopaminergic neurons in the substantia nigra.(79) Simi…”
BackgroundL’Episcopo, F., Tirolo, C., Caniglia, S., Testa, N., Morale, M. C., Serapide, M. F., Pluchino, S., & Marchetti, B. (2014) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjt053 · Cited by 80 · see citing works
“A genetic dysfunction of α-syn coupled to increased neuroinflammation can potentiate each other, driving chronic progression of neurodegeneration (Gao et al., 2011; Harm et al., 2013; Sanchez-Guajardo et al., 2013).”
BackgroundLRRK2 mediates microglial neurotoxicity via NFATc2 in rodent models of synucleinopathies
Kim, C., Beilina, A., Smith, N., Li, Y., Kim, M., Kumaran, R., Kaganovich, A., Mamais, A., Adame, A., Iba, M., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aay0399 · Cited by 79 · see citing works
Farombi, E. O., Awogbindin, I. O., Farombi, T., Oladele, J. O., Izomoh, E. R., Aladelokun, O. B., Ezekiel, I. O., Adebambo, O. I., & Abah, V. O. (2019) · NeuroToxicology · doi:10.1016/j.neuro.2019.03.005 · Cited by 79 · see citing works
Direct detection of alpha synuclein oligomers in vivo
Dimant, H., Kalia, S. K., Kalia, L. V., Zhu, L., Kibuuka, L. N., Ebrahimi‐Fakhari, D., McFarland, N. R., Fan, Z., Hyman, B. T., & McLean, P. J. (2013) · Acta Neuropathologica Communications · doi:10.1186/2051-5960-1-6 · Cited by 74 · see citing works
“Indeed this finding, taken together with accumulating evidence implicating α-syn in disease progression via a non-cell-autonomous neuroinflammatory process [29-31], led us to investigate whether inflammation occurs concomitantly with the aggregation of α-syn in the striatum and the presence of dystrophic neurites.”
BackgroundLawana, V., Singh, N., Sarkar, S., Charli, A., Jin, H., Anantharam, V., Kanthasamy, A. G., & Kanthasamy, A. (2017) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-017-9746-5 · Cited by 73 · see citing works
“In fact, chronic inflammation has been implicated in the delayed and progressive dopaminergic neurodegeneration (Gao et al. 2002a, b; Qin et al. 2007; Gao et al. 2011).”
Background
- Authors
- Gao, H.-M., Zhang, F., Zhou, H., Kam, W., Wilson, B., & Hong, J.-S.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Gao, Hui-Ming
- Venue
- Environmental Health Perspectives
- Publisher
- American Chemical Society (ACS)
- Published
- 2011-01-18
- Volume
- 119
- Issue
- 6
- Pages
- 807-814
- ISSN
- 0091-6765 (ISSN-L)
- 1552-9924
- PMC
- PMC3114815
- OpenAlex
- W1971599063
- Cited by
- 355
- References
- 46
- Citations by year
- 2026: 16 · 2025: 13 · 2024: 36 · 2023: 23 · 2022: 28 · 2021: 37 · 2020: 39 · 2019: 17 · 2018: 28 · 2017: 20 · 2016: 18 · 2015: 16 · 2014: 19 · 2013: 18 · 2012: 19
- FWCI
- 13.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- public-domain
- creativecommons.org/licenses/by/4.0/ (vor, 2537 d)
- Locations
- Environmental Health Perspectives (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Environmental Health Sciences
- 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
- Parkinson's disease, neuroinflammation, alpha-synuclein, lipopolysaccharide, two-hit model, gene-environment interaction, microglia, oxidative stress, inducible nitric oxide synthase, NADPH oxidase, dopaminergic neuron loss, nigrostriatal pathway, Lewy bodies, chronic neurodegeneration
- MeSH terms
- Amidines, Animals, Benzylamines, Disease Models, Animal, Injections, Intraperitoneal, Lipopolysaccharides, Nerve Degeneration, Onium Compounds, Parkinson Disease, Substantia Nigra, Lewy Bodies, Oxidative Stress, NADPH Oxidases, Neurodegenerative Diseases, Animals, Genetically Modified, Mice, alpha-Synuclein, Nitric Oxide Synthase Type II
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