Journal Article

DZNE-2025-00556

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Microglia and CD8+ T cell activation precede neuronal loss in a murine model of spastic paraplegia 15.

Frolov, A. (First author)DZNE* ; Huang, H. ; Schütz, D. ; Köhne, M. C.DZNE* ; Blank-Stein, N. ; Osei-Sarpong, C.DZNE* ; Büttner, M.DZNE* ; Elmzzahi, T.DZNE* ; Khundadze, M. ; Zahid, M. ; Reuter, M. ; Becker, M.DZNE* ; De Domenico, E.DZNE* ; Bonaguro, L.DZNE* ; Kallies, A. ; Morrison, H. ; Hübner, C. A. ; Händler, K.DZNE* ; Stumm, R. ; Mass, E. ; Beyer, M. D. (Last author)DZNE*

2025
Rockefeller Univ. Press New York, NY

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Please use a persistent id in citations: doi:10.1084/jem.20232357

Abstract: 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.

Keyword(s): Animals (MeSH) ; CD8-Positive T-Lymphocytes: immunology (MeSH) ; CD8-Positive T-Lymphocytes: pathology (MeSH) ; Microglia: immunology (MeSH) ; Microglia: pathology (MeSH) ; Disease Models, Animal (MeSH) ; Mice (MeSH) ; Neurons: pathology (MeSH) ; Neurons: immunology (MeSH) ; Mice, Knockout (MeSH) ; Lymphocyte Activation: immunology (MeSH) ; Spastic Paraplegia, Hereditary: immunology (MeSH) ; Spastic Paraplegia, Hereditary: pathology (MeSH) ; Mice, Inbred C57BL (MeSH)

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Contributing Institute(s):

1. Immunogenomics and Neurodegeneration (AG Beyer)
2. Clinical Single Cell Omics (CSCO) / Systems Medicine (AG Schultze)
3. Molecular and Translational Immunaging (AG Bonaguro)
4. Modular High Performance Computing and Artificial Intelligence (AG Becker)
5. Platform for Single Cell Genomics and Epigenomics (PRECISE)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)
2. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)
3. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2025

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Essential Science Indicators ; IF >= 15 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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