%0 Journal Article %1 Karikari_2022 %A Karikari, Akua A. %A McFleder, Rhonda L. %A Ribechini, Eliana %A Blum, Robert %A Bruttel, Valentin %A Knorr, Susanne %A Gehmeyr, Mona %A Volkmann, Jens %A Brotchie, Jonathan M. %A Ahsan, Fadhil %A Haack, Beatrice %A Monoranu, Camelia-Maria %A Keber, Ursula %A Yeghiazaryan, Rima %A Pagenstecher, Axel %A Heckel, Tobias %A Bischler, Thorsten %A Wischhusen, Jörg %A Koprich, James B. %A Lutz, Manfred B. %A Ip, Chi Wang %D 2022 %I Elsevier BV %J Brain, Behavior, and Immunity %K myown %P 194-210 %R https://doi.org/10.1016/j.bbi.2022.01.007 %T Neurodegeneration by α-synuclein-specific T cells in AAV-A53T-α-synuclein Parkinson's disease mice %U https://www.sciencedirect.com/science/article/pii/S0889159122000101 %V 101 %X 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 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. Keywords: Parkinson’s disease; T cells; antigen-specificity; neuroinflammation; α-synuclein.

@article{Karikari_2022, abstract = {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 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. Keywords: Parkinson’s disease; T cells; antigen-specificity; neuroinflammation; α-synuclein.}, added-at = {2024-04-16T16:33:26.000+0200}, author = {Karikari, Akua A. and McFleder, Rhonda L. and Ribechini, Eliana and Blum, Robert and Bruttel, Valentin and Knorr, Susanne and Gehmeyr, Mona and Volkmann, Jens and Brotchie, Jonathan M. and Ahsan, Fadhil and Haack, Beatrice and Monoranu, Camelia-Maria and Keber, Ursula and Yeghiazaryan, Rima and Pagenstecher, Axel and Heckel, Tobias and Bischler, Thorsten and Wischhusen, Jörg and Koprich, James B. and Lutz, Manfred B. and Ip, Chi Wang}, biburl = {https://www.bibsonomy.org/bibtex/252f4ba716a5ec86d012a2cdf31880e76/cusysmed}, day = 17, description = {Neurodegeneration by α-synuclein-specific T cells in AAV-A53T-α-synuclein Parkinson’s disease mice - ScienceDirect}, doi = {https://doi.org/10.1016/j.bbi.2022.01.007}, interhash = {d56b6197b3fb07fdf98c0abe142a9ac3}, intrahash = {52f4ba716a5ec86d012a2cdf31880e76}, issn = {0889-1591}, journal = {Brain, Behavior, and Immunity}, keywords = {myown}, month = jan, pages = {194-210}, publisher = {Elsevier BV}, timestamp = {2024-04-16T16:33:26.000+0200}, title = {Neurodegeneration by α-synuclein-specific T cells in AAV-A53T-α-synuclein Parkinson's disease mice}, type = {Publication}, url = {https://www.sciencedirect.com/science/article/pii/S0889159122000101}, volume = 101, year = 2022 }