Neurodegeneration by α-synuclein-specific T cells in AAV-A53T-α-synuclein Parkinson’s disease mice

Please always quote using this URN: urn:nbn:de:bvb:20-opus-300600
  • Background 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. Methods We utilized a mouse model of PD in which anBackground 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. Methods 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. Results 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. Conclusions 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.show moreshow less

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Author: Akua A. Karikari, Rhonda L. McFleder, Eliana Ribechini, Robert Blum, Valentin Bruttel, Susanne Knorr, Mona Gehmeyr, Jens Volkmann, Jonathan M. Brotchie, Fadhil Ahsan, Beatrice Haack, Camelia-Maria Monoranu, Ursula Keber, Rima Yeghiazaryan, Axel Pagenstecher, Tobias Heckel, Thorsten Bischler, Jörg Wischhusen, James B. Koprich, Manfred B. Lutz, Chi Wang Ip
URN:urn:nbn:de:bvb:20-opus-300600
Document Type:Journal article
Faculties:Medizinische Fakultät / Institut für Klinische Neurobiologie
Medizinische Fakultät / Pathologisches Institut
Medizinische Fakultät / Institut für Virologie und Immunbiologie
Medizinische Fakultät / Neurologische Klinik und Poliklinik
Language:English
Parent Title (English):Brain, Behavior, and Immunity
Year of Completion:2022
Volume:101
First Page:194
Last Page:210
Source:Brain, Behavior, and Immunity 2022, 101:194-210. DOI: 10.1016/j.bbi.2022.01.007
DOI:https://doi.org/10.1016/j.bbi.2022.01.007
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:Parkinson’s disease; neurodegeneration; α-synuclein-specific T cells
Release Date:2023/03/21
Collections:Open-Access-Publikationsfonds / Förderzeitraum 2022
Licence (German):License LogoCC BY-NC-ND: Creative-Commons-Lizenz: Namensnennung, Nicht kommerziell, Keine Bearbeitungen 4.0 International