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Experimental neurology2021; 346; 113845; doi: 10.1016/j.expneurol.2021.113845

Astrocyte inflammatory signaling mediates α-synuclein aggregation and dopaminergic neuronal loss following viral encephalitis.

Abstract: Viral infection of the central nervous system (CNS) can cause lasting neurological decline in surviving patients and can present with symptoms resembling Parkinson's disease (PD). The mechanisms underlying postencephalitic parkinsonism remain unclear but are thought to involve increased innate inflammatory signaling in glial cells, resulting in persistent neuroinflammation. We therefore studied the role of glial cells in regulating neuropathology in postencephalitic parkinsonism by studying the involvement of astrocytes in loss of dopaminergic neurons and aggregation of α-synuclein protein following infection with western equine encephalitis virus (WEEV). Infections were conducted in both wildtype mice and in transgenic mice lacking NFκB inflammatory signaling in astrocytes. For 2 months following WEEV infection, we analyzed glial activation, neuronal loss and protein aggregation across multiple brain regions, including the substantia nigra pars compacta (SNpc). These data revealed that WEEV induces loss of SNpc dopaminergic neurons, persistent activation of microglia and astrocytes that precipitates widespread aggregation of α-synuclein in the brain of C57BL/6 mice. Microgliosis and macrophage infiltration occurred prior to activation of astrocytes and was followed by opsonization of ⍺-synuclein protein aggregates in the cortex, hippocampus and midbrain by the complement protein, C3. Astrocyte-specific NFκB knockout mice had reduced gliosis, α-synuclein aggregate formation and neuronal loss. These data suggest that astrocytes play a critical role in initiating PD-like pathology following encephalitic infection with WEEV through innate immune inflammatory pathways that damage dopaminergic neurons, possibly by hindering clearance of ⍺-synuclein aggregates. Inhibiting glial inflammatory responses could therefore represent a potential therapy strategy for viral parkinsonism.
Copyright © 2021 Elsevier Inc. All rights reserved.
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Publication Date: 2021-08-26 PubMed ID: 34454938PubMed Central: PMC9535678DOI: 10.1016/j.expneurol.2021.113845Google Scholar: Lookup
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  • N.I.H.
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This study investigates the role of glial cells, specifically astrocytes, in the loss of dopaminergic neurons and the accumulation of α-synuclein protein which occur after infection with the Western Equine Encephalitis Virus (WEEV). The findings suggest that astrocytes may trigger inflammation that harms dopaminergic neurons and hinders α-synuclein clearance, potentially contributing to disease symptoms resembling Parkinson’s. Inhibiting these inflammatory responses could be a possible treatment strategy for viral parkinsonism.

Objective and Methodology

  • The researchers wanted to understand the mechanisms of postencephalitic parkinsonism, an illness displaying similar symptoms to Parkinson’s Disease, and thought to be caused by neuroinflammation from viral infections.
  • The experimental subjects were mice, including a genetically modified strain with impaired inflammatory responses in astrocytes, a type of glial cell.
  • The team infected mice with the Western Equine Encephalitis Virus (WEEV) and observed the cells’ reactions, paying particular attention to the glial cells’ activation and consequent effects on neurons and protein accumulation.

Research Findings

  • After infection with WEEV, the substantia nigra pars compacta (SNpc) dopaminergic neurons were lost, and α-synuclein protein aggregates formed extensively in the brains of regular C57BL/6 mice.
  • Astrocyte activation followed initial microgliosis and macrophage infiltration, and the α-synuclein protein aggregates in the brain areas were coated (“opsonized”) by a protein called C3, part of the immune system’s complement system.
  • Contrastingly, the mice genetically modified to have incapacitated astrocyte NFκB inflammatory signaling had fewer instances of glial cell activation, α-synuclein aggregation, and dopaminergic neuron loss.

Conclusion and Future Implications

  • The study’s results imply that astrocytes play a significant role in the development of PD-like symptoms post-encephalitic infection with WEEV by inciting inflammatory pathways that can negatively impact dopaminergic neurons.
  • One of these detrimental effects could be the inhibition of α-synuclein aggregates clearance, which then forms in large amounts in the brain.
  • The research’s findings could provide valuable insights for developing potential therapy strategies for viral parkinsonism, such as treatments targeting the blocking of glial inflammatory responses.

Cite This Article

APA
Bantle CM, Rocha SM, French CT, Phillips AT, Tran K, Olson KE, Bass TA, Aboellail T, Smeyne RJ, Tjalkens RB. (2021). Astrocyte inflammatory signaling mediates α-synuclein aggregation and dopaminergic neuronal loss following viral encephalitis. Exp Neurol, 346, 113845. https://doi.org/10.1016/j.expneurol.2021.113845

Publication

Experimental neurology
ISSN: 1090-2430
NlmUniqueID: 0370712
Country: United States
Language: English
Volume: 346
Pages: 113845
PII: S0014-4886(21)00253-3

Researcher Affiliations

Bantle, Collin M
  • Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, United States of America.
Rocha, Savannah M
  • Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523, United States of America.
French, C Tenley
  • Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, United States of America.
Phillips, Aaron T
  • Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, United States of America; Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523, United States of America.
Tran, Kevin
  • Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, United States of America.
Olson, Kenneth E
  • Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523, United States of America.
Bass, Todd A
  • Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523, United States of America.
Aboellail, Tawfik
  • Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523, United States of America.
Smeyne, Richard J
  • Jefferson Comprehensive Parkinson's Center, Vickie & Jack Farber Institute for Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107, United States of America.
Tjalkens, Ronald B
  • Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, United States of America. Electronic address: ron.tjalkens@colostate.edu.

MeSH Terms

  • Animals
  • Astrocytes / immunology
  • Astrocytes / metabolism
  • Dopaminergic Neurons / immunology
  • Dopaminergic Neurons / metabolism
  • Encephalitis Virus, Western Equine / immunology
  • Encephalitis Virus, Western Equine / metabolism
  • Encephalitis, Viral / immunology
  • Encephalitis, Viral / metabolism
  • Female
  • Humans
  • Inflammation Mediators / immunology
  • Inflammation Mediators / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Protein Aggregates / physiology
  • Signal Transduction / physiology
  • alpha-Synuclein / metabolism

Grant Funding

  • R01 ES030937 / NIEHS NIH HHS

Conflict of Interest Statement

Competing Interest. The authors declare no competing interest. Competing interests. The authors declare that there exist no competing interests or conflicts, disclosed or otherwise. All research and data will be made freely accessible, per the guidelines of the National Institutes of Health. Collin M. Bantle. Savannah M. Rocha. C. Tenley French. Aaron T. Phillips. Kevin Tran. Kenneth E. Olson. Todd A. Bass. Tawfik Aboellail. Richard J. Smeyne. Ronald B. Tjalkens

References

This article includes 84 references
  1. Alam G, Edler M, Burchfield S, Richardson JR. Single low doses of MPTP decrease tyrosine hydroxylase expression in the absence of overt neuron loss.. Neurotoxicology 2017 May;60:99-106.
    pmc: PMC5499677pubmed: 28377118doi: 10.1016/j.neuro.2017.03.008google scholar: lookup
  2. Anderson JP, Walker DE, Goldstein JM, de Laat R, Banducci K, Caccavello RJ, Barbour R, Huang J, Kling K, Lee M, Diep L, Keim PS, Shen X, Chataway T, Schlossmacher MG, Seubert P, Schenk D, Sinha S, Gai WP, Chilcote TJ. Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease.. J Biol Chem 2006 Oct 6;281(40):29739-52.
    pubmed: 16847063doi: 10.1074/jbc.m600933200google scholar: lookup
  3. Bantle CM, Phillips AT, Smeyne RJ, Rocha SM, Olson KE, Tjalkens RB. Infection with mosquito-borne alphavirus induces selective loss of dopaminergic neurons, neuroinflammation and widespread protein aggregation.. NPJ Parkinsons Dis 2019;5:20.
    pmc: PMC6744428pubmed: 31531390doi: 10.1038/s41531-019-0090-8google scholar: lookup
  4. Bantle CM, French CT, Cummings JE, Sadasivan S, Tran K, Slayden RA, Smeyne RJ, Tjalkens RB. Manganese exposure in juvenile C57BL/6 mice increases glial inflammatory responses in the substantia nigra following infection with H1N1 influenza virus.. PLoS One 2021;16(1):e0245171.
    pmc: PMC7833173pubmed: 33493177doi: 10.1371/journal.pone.0245171google scholar: lookup
  5. Baquet ZC, Williams D, Brody J, Smeyne RJ. A comparison of model-based (2D) and design-based (3D) stereological methods for estimating cell number in the substantia nigra pars compacta (SNpc) of the C57BL/6J mouse.. Neuroscience 2009 Jul 21;161(4):1082-90.
    pmc: PMC2705113pubmed: 19376196doi: 10.1016/j.neuroscience.2009.04.031google scholar: lookup
  6. Barcia C. Glial-mediated inflammation underlying parkinsonism.. Scientifica (Cairo) 2013;2013:357805.
    pmc: PMC3820356pubmed: 24278772doi: 10.1155/2013/357805google scholar: lookup
  7. Beatman EL, Massey A, Shives KD, Burrack KS, Chamanian M, Morrison TE, Beckham JD. Alpha-Synuclein Expression Restricts RNA Viral Infections in the Brain.. J Virol 2015 Dec 30;90(6):2767-82.
    pmc: PMC4810656pubmed: 26719256doi: 10.1128/jvi.02949-15google scholar: lookup
  8. Bodea LG, Wang Y, Linnartz-Gerlach B, Kopatz J, Sinkkonen L, Musgrove R, Kaoma T, Muller A, Vallar L, Di Monte DA, Balling R, Neumann H. Neurodegeneration by activation of the microglial complement-phagosome pathway.. J Neurosci 2014 Jun 18;34(25):8546-56.
    pmc: PMC6608212pubmed: 24948809doi: 10.1523/jneurosci.5002-13.2014google scholar: lookup
  9. Bond S, Lopez-Lloreda C, Gannon PJ, Akay-Espinoza C, Jordan-Sciutto KL. The Integrated Stress Response and Phosphorylated Eukaryotic Initiation Factor 2α in Neurodegeneration.. J Neuropathol Exp Neurol 2020 Feb 1;79(2):123-143.
    pmc: PMC6970450pubmed: 31913484doi: 10.1093/jnen/nlz129google scholar: lookup
  10. Brück D, Wenning GK, Stefanova N, Fellner L. Glia and alpha-synuclein in neurodegeneration: A complex interaction.. Neurobiol Dis 2016 Jan;85:262-274.
    pmc: PMC4730552pubmed: 25766679doi: 10.1016/j.nbd.2015.03.003google scholar: lookup
  11. Caggiu E, Arru G, Hosseini S, Niegowska M, Sechi G, Zarbo IR, Sechi LA. Inflammation, Infectious Triggers, and Parkinson's Disease.. Front Neurol 2019;10:122.
    pmc: PMC6389614pubmed: 30837941doi: 10.3389/fneur.2019.00122google scholar: lookup
  12. Chaumonnot K, Masson S, Sikner H, Bouchard A, Baverel V, Bellaye PS, Collin B, Garrido C, Kohli E. The HSP GRP94 interacts with macrophage intracellular complement C3 and impacts M2 profile during ER stress.. Cell Death Dis 2021 Jan 22;12(1):114.
    pmc: PMC7822929pubmed: 33483465doi: 10.1038/s41419-020-03288-xgoogle scholar: lookup
  13. Chida J, Hara H, Yano M, Uchiyama K, Das NR, Takahashi E, Miyata H, Tomioka Y, Ito T, Kido H, Sakaguchi S. Prion protein protects mice from lethal infection with influenza A viruses.. PLoS Pathog 2018 May;14(5):e1007049.
    pmc: PMC5953499pubmed: 29723291doi: 10.1371/journal.ppat.1007049google scholar: lookup
  14. Clarke LE, Liddelow SA, Chakraborty C, Münch AE, Heiman M, Barres BA. Normal aging induces A1-like astrocyte reactivity.. Proc Natl Acad Sci U S A 2018 Feb 20;115(8):E1896-E1905.
    pmc: PMC5828643pubmed: 29437957doi: 10.1073/pnas.1800165115google scholar: lookup
  15. Clarke P, Leser JS, Quick ED, Dionne KR, Beckham JD, Tyler KL. Death receptor-mediated apoptotic signaling is activated in the brain following infection with West Nile virus in the absence of a peripheral immune response.. J Virol 2014 Jan;88(2):1080-9.
    pmc: PMC3911655pubmed: 24198425doi: 10.1128/jvi.02944-13google scholar: lookup
  16. De Miranda BR, Popichak KA, Hammond SL, Miller JA, Safe S, Tjalkens RB. Novel para-phenyl substituted diindolylmethanes protect against MPTP neurotoxicity and suppress glial activation in a mouse model of Parkinson's disease.. Toxicol Sci 2015 Feb;143(2):360-73.
    pmc: PMC4306720pubmed: 25406165doi: 10.1093/toxsci/kfu236google scholar: lookup
  17. Dourmashkin RR. What caused the 1918-30 epidemic of encephalitis lethargica?. J R Soc Med 1997 Sep;90(9):515-20.
    pmc: PMC1296535pubmed: 9370993doi: 10.1177/014107689709000916google scholar: lookup
  18. Duffy MF, Collier TJ, Patterson JR, Kemp CJ, Luk KC, Tansey MG, Paumier KL, Kanaan NM, Fischer DL, Polinski NK, Barth OL, Howe JW, Vaikath NN, Majbour NK, El-Agnaf OMA, Sortwell CE. Lewy body-like alpha-synuclein inclusions trigger reactive microgliosis prior to nigral degeneration.. J Neuroinflammation 2018 May 1;15(1):129.
    pmc: PMC5930695pubmed: 29716614doi: 10.1186/s12974-018-1171-zgoogle scholar: lookup
  19. Earls RH, Menees KB, Chung J, Barber J, Gutekunst CA, Hazim MG, Lee JK. Intrastriatal injection of preformed alpha-synuclein fibrils alters central and peripheral immune cell profiles in non-transgenic mice.. J Neuroinflammation 2019 Dec 3;16(1):250.
    pmc: PMC6889316pubmed: 31796095doi: 10.1186/s12974-019-1636-8google scholar: lookup
  20. Eimer WA, Vijaya Kumar DK, Navalpur Shanmugam NK, Rodriguez AS, Mitchell T, Washicosky KJ, György B, Breakefield XO, Tanzi RE, Moir RD. Alzheimer's Disease-Associated β-Amyloid Is Rapidly Seeded by Herpesviridae to Protect against Brain Infection.. Neuron 2018 Jul 11;99(1):56-63.e3.
    pmc: PMC6075814pubmed: 30001512doi: 10.1016/j.neuron.2018.06.030google scholar: lookup
  21. Elizan TS, Schwartz J, Yahr MD, Casals J. Antibodies against arboviruses in postencephalitic and idiopathic Parkinson's disease.. Arch Neurol 1978 May;35(5):257-60.
    pubmed: 646678doi: 10.1001/archneur.1978.00500290003001google scholar: lookup
  22. Elizan TS, Casals J. Astrogliosis in von Economo's and postencephalitic Parkinson's diseases supports probable viral etiology.. J Neurol Sci 1991 Oct;105(2):131-4.
    pubmed: 1757788doi: 10.1016/0022-510x(91)90135-tgoogle scholar: lookup
  23. Gaskill PJ, Yano HH, Kalpana GV, Javitch JA, Berman JW. Dopamine receptor activation increases HIV entry into primary human macrophages.. PLoS One 2014;9(9):e108232.
    pmc: PMC4182469pubmed: 25268786doi: 10.1371/journal.pone.0108232google scholar: lookup
  24. Gerhard A, Pavese N, Hotton G, Turkheimer F, Es M, Hammers A, Eggert K, Oertel W, Banati RB, Brooks DJ. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson's disease.. Neurobiol Dis 2006 Feb;21(2):404-12.
    pubmed: 16182554doi: 10.1016/j.nbd.2005.08.002google scholar: lookup
  25. Gopal Krishna Patro S, Kumar Sahu K. Noramlization: A Preporcessing Stage. 2015.
  26. Gouveia K, Hurst JL. Reducing mouse anxiety during handling: effect of experience with handling tunnels.. PLoS One 2013;8(6):e66401.
    pmc: PMC3688777pubmed: 23840458doi: 10.1371/journal.pone.0066401google scholar: lookup
  27. Graeber MB, Streit WJ. Microglia: biology and pathology.. Acta Neuropathol 2010 Jan;119(1):89-105.
    pubmed: 20012873doi: 10.1007/s00401-009-0622-0google scholar: lookup
  28. Gullberg RC, Jordan Steel J, Moon SL, Soltani E, Geiss BJ. Oxidative stress influences positive strand RNA virus genome synthesis and capping.. Virology 2015 Jan 15;475:219-29.
    pmc: PMC4332586pubmed: 25514423doi: 10.1016/j.virol.2014.10.037google scholar: lookup
  29. Hammond SL, Leek AN, Richman EH, Tjalkens RB. Cellular selectivity of AAV serotypes for gene delivery in neurons and astrocytes by neonatal intracerebroventricular injection.. PLoS One 2017;12(12):e0188830.
    pmc: PMC5731760pubmed: 29244806doi: 10.1371/journal.pone.0188830google scholar: lookup
  30. Hammond SL, Popichak KA, Li X, Hunt LG, Richman EH, Damale PU, Chong EKP, Backos DS, Safe S, Tjalkens RB. The Nurr1 Ligand,1,1-bis(3'-Indolyl)-1-(p-Chlorophenyl)Methane, Modulates Glial Reactivity and Is Neuroprotective in MPTP-Induced Parkinsonism.. J Pharmacol Exp Ther 2018 Jun;365(3):636-651.
    pmc: PMC5941193pubmed: 29626009doi: 10.1124/jpet.117.246389google scholar: lookup
  31. Hayase Y, Tobita K. Influenza virus and neurological diseases.. Psychiatry Clin Neurosci 1997 Aug;51(4):181-4.
    pubmed: 9316161doi: 10.1111/j.1440-1819.1997.tb02580.xgoogle scholar: lookup
  32. Hirsch EC, Hunot S. Neuroinflammation in Parkinson's disease: a target for neuroprotection?. Lancet Neurol 2009 Apr;8(4):382-97.
    pubmed: 19296921doi: 10.1016/s1474-4422(09)70062-6google scholar: lookup
  33. Jang H, Boltz D, Sturm-Ramirez K, Shepherd KR, Jiao Y, Webster R, Smeyne RJ. Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration.. Proc Natl Acad Sci U S A 2009 Aug 18;106(33):14063-8.
    pmc: PMC2729020pubmed: 19667183doi: 10.1073/pnas.0900096106google scholar: lookup
  34. Jang H, Boltz DA, Webster RG, Smeyne RJ. Viral parkinsonism.. Biochim Biophys Acta 2009 Jul;1792(7):714-21.
    pmc: PMC4642437pubmed: 18760350doi: 10.1016/j.bbadis.2008.08.001google scholar: lookup
  35. Jellinger KA. Neuropathological aspects of Alzheimer disease, Parkinson disease and frontotemporal dementia.. Neurodegener Dis 2008;5(3-4):118-21.
    pubmed: 18322367doi: 10.1159/000113679google scholar: lookup
  36. Kirkley KS, Popichak KA, Hammond SL, Davies C, Hunt L, Tjalkens RB. Genetic suppression of IKK2/NF-κB in astrocytes inhibits neuroinflammation and reduces neuronal loss in the MPTP-Probenecid model of Parkinson's disease.. Neurobiol Dis 2019 Jul;127:193-209.
    pmc: PMC6588478pubmed: 30818064doi: 10.1016/j.nbd.2019.02.020google scholar: lookup
  37. Kostuk EW, Cai J, Iacovitti L. Subregional differences in astrocytes underlie selective neurodegeneration or protection in Parkinson's disease models in culture.. Glia 2019 Aug;67(8):1542-1557.
    pmc: PMC6594409pubmed: 31025779doi: 10.1002/glia.23627google scholar: lookup
  38. Lesteberg KE, Beckham JD. Immunology of West Nile Virus Infection and the Role of Alpha-Synuclein as a Viral Restriction Factor.. Viral Immunol 2019 Jan Feb;32(1):38-47.
    pubmed: 30222521doi: 10.1089/vim.2018.0075google scholar: lookup
  39. Lewy FH. Die Entstehung der Einschlußkörper und ihre Bedeutung für die systematische Einordnung der sogenannten Viruskrankheiten. Deutsche Zeitschrift für Nervenheilkunde 1932;124:93–100.
  40. Lian H, Yang L, Cole A, Sun L, Chiang AC, Fowler SW, Shim DJ, Rodriguez-Rivera J, Taglialatela G, Jankowsky JL, Lu HC, Zheng H. NFκB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer's disease.. Neuron 2015 Jan 7;85(1):101-115.
    pmc: PMC4289109pubmed: 25533482doi: 10.1016/j.neuron.2014.11.018google scholar: lookup
  41. Lian H, Litvinchuk A, Chiang AC, Aithmitti N, Jankowsky JL, Zheng H. Astrocyte-Microglia Cross Talk through Complement Activation Modulates Amyloid Pathology in Mouse Models of Alzheimer's Disease.. J Neurosci 2016 Jan 13;36(2):577-89.
    pmc: PMC4710776pubmed: 26758846doi: 10.1523/jneurosci.2117-15.2016google scholar: lookup
  42. Liddelow SA, Barres BA. Reactive Astrocytes: Production, Function, and Therapeutic Potential.. Immunity 2017 Jun 20;46(6):957-967.
    pubmed: 28636962doi: 10.1016/j.immuni.2017.06.006google scholar: lookup
  43. Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, Bennett ML, Münch AE, Chung WS, Peterson TC, Wilton DK, Frouin A, Napier BA, Panicker N, Kumar M, Buckwalter MS, Rowitch DH, Dawson VL, Dawson TM, Stevens B, Barres BA. Neurotoxic reactive astrocytes are induced by activated microglia.. Nature 2017 Jan 26;541(7638):481-487.
    pmc: PMC5404890pubmed: 28099414doi: 10.1038/nature21029google scholar: lookup
  44. Lindqvist D, Hall S, Surova Y, Nielsen HM, Janelidze S, Brundin L, Hansson O. Cerebrospinal fluid inflammatory markers in Parkinson's disease--associations with depression, fatigue, and cognitive impairment.. Brain Behav Immun 2013 Oct;33:183-9.
    pubmed: 23911592doi: 10.1016/j.bbi.2013.07.007google scholar: lookup
  45. Linnartz B, Neumann H. Microglial activatory (immunoreceptor tyrosine-based activation motif)- and inhibitory (immunoreceptor tyrosine-based inhibition motif)-signaling receptors for recognition of the neuronal glycocalyx.. Glia 2013 Jan;61(1):37-46.
    pubmed: 22615186doi: 10.1002/glia.22359google scholar: lookup
  46. Liu C, Voth DW, Rodina P, Shauf LR, Gonzalez G. A comparative study of the pathogenesis of western equine and eastern equine encephalomyelitis viral infections in mice by intracerebral and subcutaneous inoculations.. J Infect Dis 1970 Jul-Aug;122(1):53-63.
    pubmed: 4914943doi: 10.1093/infdis/122.1-2.53google scholar: lookup
  47. Loeffler DA, Camp DM, Conant SB. Complement activation in the Parkinson's disease substantia nigra: an immunocytochemical study.. J Neuroinflammation 2006 Oct 19;3:29.
    pmc: PMC1626447pubmed: 17052351doi: 10.1186/1742-2094-3-29google scholar: lookup
  48. Logue CH, Bosio CF, Welte T, Keene KM, Ledermann JP, Phillips A, Sheahan BJ, Pierro DJ, Marlenee N, Brault AC, Bosio CM, Singh AJ, Powers AM, Olson KE. Virulence variation among isolates of western equine encephalitis virus in an outbred mouse model.. J Gen Virol 2009 Aug;90(Pt 8):1848-1858.
    pmc: PMC2887574pubmed: 19403754doi: 10.1099/vir.0.008656-0google scholar: lookup
  49. Malik R, Gogna A, Meher J, Singh KK, Sharma SK. Dengue encephalopathy - still an enigma?. J Infect Dev Ctries 2014 Aug 13;8(8):1076-8.
    pubmed: 25116679doi: 10.3855/jidc.4762google scholar: lookup
  50. Martinez EM, Young AL, Patankar YR, Berwin BL, Wang L, von Herrmann KM, Weier JM, Havrda MC. Editor's Highlight: Nlrp3 Is Required for Inflammatory Changes and Nigral Cell Loss Resulting From Chronic Intragastric Rotenone Exposure in Mice.. Toxicol Sci 2017 Sep 1;159(1):64-75.
    pmc: PMC5837210pubmed: 28903492doi: 10.1093/toxsci/kfx117google scholar: lookup
  51. Mattson MP. Infectious agents and age-related neurodegenerative disorders.. Ageing Res Rev 2004 Jan;3(1):105-20.
    pmc: PMC7172323pubmed: 15163105doi: 10.1016/j.arr.2003.08.005google scholar: lookup
  52. McCall S, Henry JM, Reid AH, Taubenberger JK. Influenza RNA not detected in archival brain tissues from acute encephalitis lethargica cases or in postencephalitic Parkinson cases.. J Neuropathol Exp Neurol 2001 Jul;60(7):696-704.
    pubmed: 11444798doi: 10.1093/jnen/60.7.696google scholar: lookup
  53. Miller JA, Runkle SA, Tjalkens RB, Philbert MA. 1,3-Dinitrobenzene-induced metabolic impairment through selective inactivation of the pyruvate dehydrogenase complex.. Toxicol Sci 2011 Aug;122(2):502-11.
    pmc: PMC3155080pubmed: 21551353doi: 10.1093/toxsci/kfr102google scholar: lookup
  54. Mogi M, Harada M, Narabayashi H, Inagaki H, Minami M, Nagatsu T. Interleukin (IL)-1 beta, IL-2, IL-4, IL-6 and transforming growth factor-alpha levels are elevated in ventricular cerebrospinal fluid in juvenile parkinsonism and Parkinson's disease.. Neurosci Lett 1996 Jun 14;211(1):13-6.
    pubmed: 8809836doi: 10.1016/0304-3940(96)12706-3google scholar: lookup
  55. MULDER DW, PARROTT M, THALER M. Sequelae of western equine encephalitis.. Neurology 1951 Jul-Aug;1(4):318-27.
    pubmed: 14853039doi: 10.1212/wnl.1.7-8.318google scholar: lookup
  56. Nouraei N, Mason DM, Miner KM, Carcella MA, Bhatia TN, Dumm BK, Soni D, Johnson DA, Luk KC, Leak RK. Critical appraisal of pathology transmission in the α-synuclein fibril model of Lewy body disorders.. Exp Neurol 2018 Jan;299(Pt A):172-196.
    pmc: PMC5736319pubmed: 29056362doi: 10.1016/j.expneurol.2017.10.017google scholar: lookup
  57. Pacelli C, Giguère N, Bourque MJ, Lévesque M, Slack RS, Trudeau LÉ. Elevated Mitochondrial Bioenergetics and Axonal Arborization Size Are Key Contributors to the Vulnerability of Dopamine Neurons.. Curr Biol 2015 Sep 21;25(18):2349-60.
    pubmed: 26320949doi: 10.1016/j.cub.2015.07.050google scholar: lookup
  58. PALMER RJ, FINLEY KH. Sequelae of encephalitis; report of a study after the California epidemic.. Calif Med 1956 Feb;84(2):98-100.
    pmc: PMC1532844pubmed: 13284639
  59. Phillips AT, Stauft CB, Aboellail TA, Toth AM, Jarvis DL, Powers AM, Olson KE. Bioluminescent imaging and histopathologic characterization of WEEV neuroinvasion in outbred CD-1 mice.. PLoS One 2013;8(1):e53462.
    pmc: PMC3534643pubmed: 23301074doi: 10.1371/journal.pone.0053462google scholar: lookup
  60. Phillips AT, Rico AB, Stauft CB, Hammond SL, Aboellail TA, Tjalkens RB, Olson KE. Entry Sites of Venezuelan and Western Equine Encephalitis Viruses in the Mouse Central Nervous System following Peripheral Infection.. J Virol 2016 Jun 15;90(12):5785-96.
    pmc: PMC4886771pubmed: 27053560doi: 10.1128/jvi.03219-15google scholar: lookup
  61. Popichak KA, Afzali MF, Kirkley KS, Tjalkens RB. Glial-neuronal signaling mechanisms underlying the neuroinflammatory effects of manganese.. J Neuroinflammation 2018 Nov 21;15(1):324.
    pmc: PMC6247759pubmed: 30463564doi: 10.1186/s12974-018-1349-4google scholar: lookup
  62. Readhead B, Haure-Mirande JV, Funk CC, Richards MA, Shannon P, Haroutunian V, Sano M, Liang WS, Beckmann ND, Price ND, Reiman EM, Schadt EE, Ehrlich ME, Gandy S, Dudley JT. Multiscale Analysis of Independent Alzheimer's Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus.. Neuron 2018 Jul 11;99(1):64-82.e7.
    pmc: PMC6551233pubmed: 29937276doi: 10.1016/j.neuron.2018.05.023google scholar: lookup
  63. Reid AH, McCall S, Henry JM, Taubenberger JK. Experimenting on the past: the enigma of von Economo's encephalitis lethargica.. J Neuropathol Exp Neurol 2001 Jul;60(7):663-70.
    pubmed: 11444794doi: 10.1093/jnen/60.7.663google scholar: lookup
  64. Rey NL, Steiner JA, Maroof N, Luk KC, Madaj Z, Trojanowski JQ, Lee VM, Brundin P. Widespread transneuronal propagation of α-synucleinopathy triggered in olfactory bulb mimics prodromal Parkinson's disease.. J Exp Med 2016 Aug 22;213(9):1759-78.
    pmc: PMC4995088pubmed: 27503075doi: 10.1084/jem.20160368google scholar: lookup
  65. Rey NL, George S, Steiner JA, Madaj Z, Luk KC, Trojanowski JQ, Lee VM, Brundin P. Spread of aggregates after olfactory bulb injection of α-synuclein fibrils is associated with early neuronal loss and is reduced long term.. Acta Neuropathol 2018 Jan;135(1):65-83.
    pmc: PMC5756266pubmed: 29209768doi: 10.1007/s00401-017-1792-9google scholar: lookup
  66. Sadasivan S, Pond BB, Pani AK, Qu C, Jiao Y, Smeyne RJ. Methylphenidate exposure induces dopamine neuron loss and activation of microglia in the basal ganglia of mice.. PLoS One 2012;7(3):e33693.
    pmc: PMC3312333pubmed: 22470460doi: 10.1371/journal.pone.0033693google scholar: lookup
  67. Sadasivan S, Zanin M, O'Brien K, Schultz-Cherry S, Smeyne RJ. Induction of microglia activation after infection with the non-neurotropic A/CA/04/2009 H1N1 influenza virus.. PLoS One 2015;10(4):e0124047.
    pmc: PMC4393251pubmed: 25861024doi: 10.1371/journal.pone.0124047google scholar: lookup
  68. Sadasivan S, Sharp B, Schultz-Cherry S, Smeyne RJ. Synergistic effects of influenza and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can be eliminated by the use of influenza therapeutics: experimental evidence for the multi-hit hypothesis.. NPJ Parkinsons Dis 2017;3:18.
    pmc: PMC5460228pubmed: 28649618doi: 10.1038/s41531-017-0019-zgoogle scholar: lookup
  69. Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, Ransohoff RM, Greenberg ME, Barres BA, Stevens B. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner.. Neuron 2012 May 24;74(4):691-705.
    pmc: PMC3528177pubmed: 22632727doi: 10.1016/j.neuron.2012.03.026google scholar: lookup
  70. Schultz DR, Barthal JS, Garrett G. Western equine encephalitis with rapid onset of parkinsonism.. Neurology 1977 Nov;27(11):1095-6.
    pubmed: 563006doi: 10.1212/wnl.27.11.1095google scholar: lookup
  71. Shi Q, Chowdhury S, Ma R, Le KX, Hong S, Caldarone BJ, Stevens B, Lemere CA. Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice.. Sci Transl Med 2017 May 31;9(392).
    pmc: PMC6936623pubmed: 28566429doi: 10.1126/scitranslmed.aaf6295google scholar: lookup
  72. Silva da Costa L, Pereira da Silva AP, Da Poian AT, El-Bacha T. Mitochondrial bioenergetic alterations in mouse neuroblastoma cells infected with Sindbis virus: implications to viral replication and neuronal death.. PLoS One 2012;7(4):e33871.
    pmc: PMC3317446pubmed: 22485151doi: 10.1371/journal.pone.0033871google scholar: lookup
  73. Simanjuntak Y, Liang JJ, Lee YL, Lin YL. Japanese Encephalitis Virus Exploits Dopamine D2 Receptor-phospholipase C to Target Dopaminergic Human Neuronal Cells.. Front Microbiol 2017;8:651.
    pmc: PMC5387065pubmed: 28443089doi: 10.3389/fmicb.2017.00651google scholar: lookup
  74. Smeyne RJ, Breckenridge CB, Beck M, Jiao Y, Butt MT, Wolf JC, Zadory D, Minnema DJ, Sturgess NC, Travis KZ, Cook AR, Smith LL, Botham PA. Assessment of the Effects of MPTP and Paraquat on Dopaminergic Neurons and Microglia in the Substantia Nigra Pars Compacta of C57BL/6 Mice.. PLoS One 2016;11(10):e0164094.
    pmc: PMC5082881pubmed: 27788145doi: 10.1371/journal.pone.0164094google scholar: lookup
  75. Stolzenberg E, Berry D, Yang D, Lee EY, Kroemer A, Kaufman S, Wong GCL, Oppenheim JJ, Sen S, Fishbein T, Bax A, Harris B, Barbut D, Zasloff MA. A Role for Neuronal Alpha-Synuclein in Gastrointestinal Immunity.. J Innate Immun 2017;9(5):456-463.
    pmc: PMC5865636pubmed: 28651250doi: 10.1159/000477990google scholar: lookup
  76. Stuart SA, Robinson ES. Reducing the stress of drug administration: implications for the 3Rs.. Sci Rep 2015 Sep 23;5:14288.
    pmc: PMC4585806pubmed: 26395864doi: 10.1038/srep14288google scholar: lookup
  77. Tansey MG. Inflammation in neuropsychiatric disease.. Neurobiol Dis 2010 Mar;37(3):491-2.
    pmc: PMC2948858pubmed: 20005951doi: 10.1016/j.nbd.2009.12.004google scholar: lookup
  78. Tapias V, Greenamyre JT, Watkins SC. Automated imaging system for fast quantitation of neurons, cell morphology and neurite morphometry in vivo and in vitro.. Neurobiol Dis 2013 Jun;54:158-68.
    pmc: PMC3604080pubmed: 23220621doi: 10.1016/j.nbd.2012.11.018google scholar: lookup
  79. Vasek MJ, Garber C, Dorsey D, Durrant DM, Bollman B, Soung A, Yu J, Perez-Torres C, Frouin A, Wilton DK, Funk K, DeMasters BK, Jiang X, Bowen JR, Mennerick S, Robinson JK, Garbow JR, Tyler KL, Suthar MS, Schmidt RE, Stevens B, Klein RS. A complement-microglial axis drives synapse loss during virus-induced memory impairment.. Nature 2016 Jun 23;534(7608):538-43.
    pmc: PMC5452615pubmed: 27337340doi: 10.1038/nature18283google scholar: lookup
  80. Wang Q, Xin X, Wang T, Wan J, Ou Y, Yang Z, Yu Q, Zhu L, Guo Y, Wu Y, Ding Z, Zhang Y, Pan Z, Tang Y, Li S, Kong L. Japanese Encephalitis Virus Induces Apoptosis and Encephalitis by Activating the PERK Pathway.. J Virol 2019 Sep 1;93(17).
    pmc: PMC6694805pubmed: 31189710doi: 10.1128/jvi.00887-19google scholar: lookup
  81. Yeh JX, Park E, Schultz KLW, Griffin DE. NF-κB Activation Promotes Alphavirus Replication in Mature Neurons.. J Virol 2019 Dec 15;93(24).
    pmc: PMC6880171pubmed: 31554691doi: 10.1128/jvi.01071-19google scholar: lookup
  82. Zhang Y, Hoppe AD, Swanson JA. Coordination of Fc receptor signaling regulates cellular commitment to phagocytosis.. Proc Natl Acad Sci U S A 2010 Nov 9;107(45):19332-7.
    pmc: PMC2984174pubmed: 20974965doi: 10.1073/pnas.1008248107google scholar: lookup
  83. Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O'Keeffe S, Phatnani HP, Guarnieri P, Caneda C, Ruderisch N, Deng S, Liddelow SA, Zhang C, Daneman R, Maniatis T, Barres BA, Wu JQ. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex.. J Neurosci 2014 Sep 3;34(36):11929-47.
    pmc: PMC4152602pubmed: 25186741doi: 10.1523/jneurosci.1860-14.2014google scholar: lookup
  84. Zhu L, Ly H, Liang Y. PLC-γ1 signaling plays a subtype-specific role in postbinding cell entry of influenza A virus.. J Virol 2014 Jan;88(1):417-24.
    pmc: PMC3911727pubmed: 24155396doi: 10.1128/jvi.02591-13google scholar: lookup

Citations

This article has been cited 20 times.
  1. Rocha SM, Kirkley KS, Chatterjee D, Aboellail TA, Smeyne RJ, Tjalkens RB. Microglia-specific knock-out of NF-κB/IKK2 increases the accumulation of misfolded α-synuclein through the inhibition of p62/sequestosome-1-dependent autophagy in the rotenone model of Parkinson's disease. Glia 2023 Sep;71(9):2154-2179.
    doi: 10.1002/glia.24385pubmed: 37199240google scholar: lookup
  2. Behnia M, Bradfute SB. The Host Non-Coding RNA Response to Alphavirus Infection. Viruses 2023 Feb 18;15(2).
    doi: 10.3390/v15020562pubmed: 36851776google scholar: lookup
  3. Jorgačevski J, Potokar M. Immune Functions of Astrocytes in Viral Neuroinfections. Int J Mol Sci 2023 Feb 9;24(4).
    doi: 10.3390/ijms24043514pubmed: 36834929google scholar: lookup
  4. Davé VA, Klein RS. The multitaskers of the brain: Glial responses to viral infections and associated post-infectious neurologic sequelae. Glia 2023 Apr;71(4):803-818.
    doi: 10.1002/glia.24294pubmed: 36334073google scholar: lookup
  5. Szego EM, Malz L, Bernhardt N, Rösen-Wolff A, Falkenburger BH, Luksch H. Constitutively active STING causes neuroinflammation and degeneration of dopaminergic neurons in mice. Elife 2022 Oct 31;11.
    doi: 10.7554/eLife.81943pubmed: 36314770google scholar: lookup
  6. Rocha SM, Bantle CM, Aboellail T, Chatterjee D, Smeyne RJ, Tjalkens RB. Rotenone induces regionally distinct α-synuclein protein aggregation and activation of glia prior to loss of dopaminergic neurons in C57Bl/6 mice. Neurobiol Dis 2022 Jun 1;167:105685.
    doi: 10.1016/j.nbd.2022.105685pubmed: 35257879google scholar: lookup
  7. Shen S, Zhang C, Xu YM, Shi CH. The Role of Pathogens and Anti-Infective Agents in Parkinson's Disease, from Etiology to Therapeutic Implications. J Parkinsons Dis 2022;12(1):27-44.
    doi: 10.3233/JPD-212929pubmed: 34719435google scholar: lookup
  8. Kędzia D, Galita G, Majsterek I, Rozpędek-Kamińska W. Microglia, Astrocytes, and Oligodendrocytes in Parkinson's Disease: Neuroinflammatory Crosstalk and Emerging Therapeutic Strategies. Biomolecules 2026 Jan 15;16(1).
    doi: 10.3390/biom16010156pubmed: 41594697google scholar: lookup
  9. Wang L, Zheng R, Li Z, Zhang L. Western equine encephalitis virus: A comprehensive review of epidemics, transmission, hosts, and strategies for mitigation. Virulence 2025 Dec;16(1):2580162.
    doi: 10.1080/21505594.2025.2580162pubmed: 41178425google scholar: lookup
  10. Veiga-Lopez A, Stevens HE, Rand M, Tjalkens R, Claus Henn B, Marsit CJ, Bernstein AI, Bonner MR, Hoffmann HM, Meliker JR. Reflections on the NIEHS Virtual Consortium funding mechanism (ViCTER) and what it has taught us about the future of transdisciplinary science. Toxicology 2025 Dec;518:154283.
    doi: 10.1016/j.tox.2025.154283pubmed: 40972998google scholar: lookup
  11. Rodríguez-Castañeda M, Campos-Ríos A, Lamas JA, Covelo A. Astrocyte alterations in α-synucleinopathies. Front Cell Neurosci 2025;19:1650326.
    doi: 10.3389/fncel.2025.1650326pubmed: 40842565google scholar: lookup
  12. Lau VZ, Awogbindin IO, Frenkel D, Whitehead SN, Tremblay MÈ. A hypothesis explaining Alzheimer's disease, Parkinson's disease, and dementia with Lewy bodies overlap. Alzheimers Dement 2025 Jun;21(6):e70363.
    doi: 10.1002/alz.70363pubmed: 40528299google scholar: lookup
  13. Woodson CM, Carney SK, Kehn-Hall K. Neuropathogenesis of Encephalitic Alphaviruses in Non-Human Primate and Mouse Models of Infection. Pathogens 2025 Feb 14;14(2).
    doi: 10.3390/pathogens14020193pubmed: 40005568google scholar: lookup
  14. Isonaka R, Sullivan P, Goldstein DS. Pathophysiological Significance of α-Synuclein in Sympathetic Nerves: In Vivo Observations. Neurology 2025 Feb 11;104(3):e210215.
    doi: 10.1212/WNL.0000000000210215pubmed: 39805051google scholar: lookup
  15. VanderGiessen M, de Jager C, Leighton J, Xie H, Theus M, Johnson E, Kehn-Hall K. Neurological manifestations of encephalitic alphaviruses, traumatic brain injuries, and organophosphorus nerve agent exposure. Front Neurosci 2024;18:1514940.
    doi: 10.3389/fnins.2024.1514940pubmed: 39734493google scholar: lookup
  16. Al-Musawi I, Dennis BH, Clowry GJ, LeBeau FEN. Evidence for prodromal changes in neuronal excitability and neuroinflammation in the hippocampus in young alpha-synuclein (A30P) transgenic mice. Front Dement 2024;3:1404841.
    doi: 10.3389/frdem.2024.1404841pubmed: 39081599google scholar: lookup
  17. Pavlou A, Mulenge F, Gern OL, Busker LM, Greimel E, Waltl I, Kalinke U. Orchestration of antiviral responses within the infected central nervous system. Cell Mol Immunol 2024 Sep;21(9):943-958.
    doi: 10.1038/s41423-024-01181-7pubmed: 38997413google scholar: lookup
  18. Schreiber CS, Wiesweg I, Stanelle-Bertram S, Beck S, Kouassi NM, Schaumburg B, Gabriel G, Richter F, Käufer C. Sex-specific biphasic alpha-synuclein response and alterations of interneurons in a COVID-19 hamster model. EBioMedicine 2024 Jul;105:105191.
    doi: 10.1016/j.ebiom.2024.105191pubmed: 38865747google scholar: lookup
  19. Markovic M, Yeapuri P, Namminga KL, Lu Y, Saleh M, Olson KE, Gendelman HE, Mosley RL. Interleukin-2 expands neuroprotective regulatory T cells in Parkinson's disease. NeuroImmune Pharm Ther 2022 Mar;1(1):43-50.
    doi: 10.1515/nipt-2022-0001pubmed: 38407500google scholar: lookup
  20. Zhao YJ, Xu KF, Shu FX, Zhang F. Neurotropic virus infection and neurodegenerative diseases: Potential roles of autophagy pathway. CNS Neurosci Ther 2024 Jun;30(6):e14548.
    doi: 10.1111/cns.14548pubmed: 38082503google scholar: lookup
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