Microglia and CD8+ T cell activation precede neuronal loss in a murine model of spastic paraplegia 15
In central nervous system (CNS) diseases characterized by late-onset neurodegeneration, the interplay between innate and adaptive immune responses remains poorly understood. This knowledge gap is exacerbated by the prolonged protracted disease course as it complicates the delineation of brain-resident and infiltrating cells. Here, we conducted comprehensive profiling of innate and adaptive immune cells in a murine model of spastic paraplegia 15 (SPG15), a complicated form of hereditary spastic paraplegia. Using fate-mapping of bone marrow-derived cells, we identified microgliosis accompanied by infiltration and local expansion of T cells in the CNS of Spg15-/- mice. Single-cell analysis revealed an expansion of disease-associated microglia (DAM) and effector CD8+ T cells prior to neuronal loss. Analysis of potential cell-cell communication pathways suggested bidirectional interactions between DAM and effector CD8+ T cells, potentially contributing to disease progression in Spg15-/- mice. In summary, we identified a shift in microglial phenotypes associated with the recruitment and expansion of T cells as a new characteristic of Spg15-driven neuropathology.
Authors
- Helen Morrison (ORCID: https://orcid.org/0000-0003-4938-1409)
- Maren Büttner (ORCID: https://orcid.org/0000-0002-6189-3792)
- Ralf Stumm (ORCID: https://orcid.org/0000-0002-9458-5526)
- Axel Kallies (ORCID: https://orcid.org/0000-0002-6312-6968)
- Marc Beyer (ORCID: https://orcid.org/0000-0001-9704-148X)
- Nelli Blank (ORCID: https://orcid.org/0000-0003-2258-736X)
- Maren Köhne
- Collins Osei-Sarpong (ORCID: https://orcid.org/0000-0002-1093-5147)
- Tarek Elmzzahi (ORCID: https://orcid.org/0000-0003-1168-8114)
- Mukhran Khundadze (ORCID: https://orcid.org/0000-0002-7642-7671)
- Elena De Domenico (ORCID: https://orcid.org/0000-0003-0336-8284)
- Hao Huang (ORCID: https://orcid.org/0000-0003-3878-3947)
- Kristian Händler (ORCID: https://orcid.org/0000-0001-5273-5277)
- Matthias Becker (ORCID: https://orcid.org/0000-0002-7120-4508)
- Elvira Mass (ORCID: https://orcid.org/0000-0003-2318-2356)
- Lorenzo Bonaguro (ORCID: https://orcid.org/0000-0001-9675-7208)
- A. N. FROLOV (ORCID: https://orcid.org/0000-0002-4406-1206)
- Michael Reuter
- Christian A. Hübner
- Dagmar Schütz
- M. Shamim H. Zahid
Institutions
- University of Bonn (DE)
- The University of Melbourne (AU)
- University of Münster (DE)
- German Center for Neurodegenerative Diseases (DE)
- Peter Doherty Institute (AU)
- University Hospital Schleswig-Holstein (DE)
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) (DE)
- Jena University Hospital (DE)
- Institute of Pharmacology (CZ)
- Friedrich Schiller University Jena (DE)
- Charité - Universitätsmedizin Berlin (DE)
- Epigenomics (Germany) (DE)
- University of Lübeck (DE)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2025-04-23
- DOI
- https://doi.org/10.1084/jem.20232357
- Citations
- 7
- Primary Topic
- Hereditary Neurological Disorders
- Type
- article
- Field-Weighted Citation Impact
- 6.36
Funders
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- European Research Council
- Leibniz-Gemeinschaft