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. 2022 Mar:101:194-210.
doi: 10.1016/j.bbi.2022.01.007. Epub 2022 Jan 12.

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

Akua A Karikari  1 , Rhonda L McFleder  1 , Eliana Ribechini  2 , Robert Blum  3 , Valentin Bruttel  4 , Susanne Knorr  1 , Mona Gehmeyr  1 , Jens Volkmann  1 , Jonathan M Brotchie  5 , Fadhil Ahsan  4 , Beatrice Haack  4 , Camelia-Maria Monoranu  6 , Ursula Keber  7 , Rima Yeghiazaryan  7 , Axel Pagenstecher  7 , Tobias Heckel  8 , Thorsten Bischler  8 , Jörg Wischhusen  4 , James B Koprich  5 , Manfred B Lutz  9 , Chi Wang Ip  10
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Free article

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

Akua A Karikari et al. Brain Behav Immun. 2022 Mar.
Free article

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: Antigen-specificity; Neuroinflammation; Parkinson’s disease; T cells; α-synuclein.

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