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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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“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]
In the citing paper
“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]
In the citing paper
“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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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
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 119
“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 122
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 116
“…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 120
“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 129
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
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 129
“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 118
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
“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 111
“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 109
“[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 105
Arneth, B. M. (2018) · Postgraduate Medical Journal · doi:10.1136/postgradmedj-2017-135424 · Cited by 112
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
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 99
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 103
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
“…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
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 96
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
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
“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 92
“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 86
“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 88
“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 91
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., Fejtova, A., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0385-4 · Cited by 86
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 85
“…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 86
“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 87
“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 85
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
“…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 85
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
Lim, J., Bang, Y., & Choi, H. J. (2018) · Archives of Pharmacal Research · doi:10.1007/s12272-018-1063-x · Cited by 82
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 85
“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 83
“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
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
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 76
“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
“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
Metadata
- 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 › 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, 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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