Neurodegeneration by α-synuclein-specific T cells in AAV-A53T-α-synuclein Parkinson’s disease mice
Open accessAbstract
Antigen-specific neuroinflammation and neurodegeneration are characteristic for neuroimmunological diseases. In Parkinson’s disease (PD) pathogenesis, α-synuclein is a known culprit. Evidence for α-synuclein-specific T cell responses was recently obtained in PD. Still, a causative link between these α-synuclein responses and dopaminergic neurodegeneration had been lacking. We thus addressed the functional relevance of α-synuclein-specific immune responses in PD in a mouse model. We utilized a mouse model of PD in which an Adeno-associated Vector 1/2 serotype (AAV1/2) expressing human mutated A53T-α-Synuclein was stereotactically injected into the substantia nigra (SN) of either wildtype C57BL/6 or Recombination-activating gene 1 (RAG1)-/- mice. Brain, spleen, and lymph node tissues from different time points following injection were then analyzed via FACS, cytokine bead assay, immunohistochemistry and RNA-sequencing to determine the role of T cells and inflammation in this model. Bone marrow transfer from either CD4+/CD8-, CD4-/CD8+, or CD4+/CD8+ (JHD-/-) mice into the RAG-1-/- mice was also employed. In addition to the in vivo studies, a newly developed A53T-α-synuclein-expressing neuronal cell culture/immune cell assay was utilized. AAV-based overexpression of pathogenic human A53T-α-synuclein in dopaminergic neurons of the SN stimulated T cell infiltration. RNA-sequencing of immune cells from PD mouse brains confirmed a pro-inflammatory gene profile. T cell responses were directed against A53T-α-synuclein-peptides in the vicinity of position 53 (68–78) and surrounding the pathogenically relevant S129 (120–134). T cells were required for α-synuclein-induced neurodegeneration in vivo and in vitro, while B cell deficiency did not protect from dopaminergic neurodegeneration. Using T cell and/or B cell deficient mice and a newly developed A53T-α-synuclein-expressing neuronal cell culture/immune cell assay, we confirmed in vivo and in vitro that pathogenic α-synuclein peptide-specific T cell responses can cause dopaminergic neurodegeneration and thereby contribute to PD-like pathology.
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High number of T cells response to α-synuclein were found in brain of PD patients and mouse model.
“A high number of T cells response to α-synuclein were found in the brain of PD patients and mouse model.”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [76]
Microglia activation by α-synuclein aggregates or other factors can increase MHC I expression on neurons, enhance presentation of α-synuclein antigens by neurons, which are subsequently killed by α-synuclein reactive T cells.
“Microglia activation by α-synuclein aggregates or other factors can increase the expression of MHC I expression on neurons, enhance the presentation of α-synuclein antigens by neurons, which were subsequently killed by α-synuclein reactive T cells.74–76”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [76]
Adaptive immune system plays an important role in approximately 40% of PD.
“Recently, numerous evidences suggest that adaptive immune system plays important role in approximately 40% PD.”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [76]
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- Authors
- Karikari, A. A., McFleder, R. L., Ribechini, E., Blum, R., Bruttel, V., Knorr, S., Gehmeyr, M., Volkmann, J., Brotchie, J. M., Ahsan, F., Haack, B., Monoranu, C.-M., Keber, U., Yeghiazaryan, R., Pagenstecher, A., Heckel, T., Bischler, T., Wischhusen, J., Koprich, J. B., Lutz, M. B., & Ip, C. W.
- Affiliations
- Universitätsklinikum Würzburg (DE)
- University of Würzburg (DE)
- University Health Network (CA)
- Philipps University of Marburg (DE)
- Corresponding author
- Lutz, Manfred B.
- ORCID
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2022-03
- Volume
- 101
- Pages
- 194-210
- ISSN
- 0889-1591 (ISSN-L)
- OpenAlex
- W4205133460
- Cited by
- 116
- References
- 13
- Citations by year
- 2026: 21 · 2025: 25 · 2024: 37 · 2023: 23 · 2022: 10
- FWCI
- 12.89
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Brain Behavior and Immunity (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Online Publication Service of Würzburg University (Würzburg University) (submittedVersion, cc-by-nc-nd)
- Funders
- Deutsche Forschungsgemeinschaft (424778381-TRR 295 (A06)
- Horizon 2020
- Stiftung VERUM
- Deutsche Stiftung Neurologie
- Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum Würzburg
- Alexander von Humboldt-Stiftung
- Deutscher Akademischer Austauschdienst
- Julius-Maximilians-Universität Würzburg (Z-6, A-303, A-421, N-362)
- 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, alpha-synuclein, A53T mutation, dopaminergic neuron loss, neuroinflammation, antigen-specific T cell responses, substantia nigra, Rag1-deficient mice, B cell deficiency, T cell subsets
- MeSH terms
- Animals, Disease Models, Animal, Dopamine, Mice, Inbred C57BL, Mice, Transgenic, Parkinson Disease, RNA, Substantia Nigra, T-Lymphocytes, Mice, alpha-Synuclein, Dopaminergic Neurons
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