Microglia and CD8+ T cell activation precede neuronal loss in a murine model of spastic paraplegia 15

• DOI: 10.1084/jem.20232357
• Publication Date: 2025-04-23T14:09:17Z
• Authors: Aleksej Frolov; Hao Huang; Dagmar Schütz; Maren Köhne; Nelli Blank-Stein; Collins Osei-Sarpong; Maren Büttner; Tarek Elmzzahi; Mukhran Khundadze; Marina Zahid; Michael Reuter; Matthias Becker; Elena De Domenico; Lorenzo Bonaguro; Axel Kallies; Helen Morrison; Christian A. Hübner; Kristian Händler; Ralf Stumm; Elvira Mass; Marc D. Beyer

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 prolonged protracted disease course as it complicates delineation of brain-resident infiltrating cells. Here, we conducted comprehensive profiling cells in a murine model spastic paraplegia 15 (SPG15), complicated form hereditary paraplegia. Using fate-mapping bone marrow–derived cells, identified microgliosis accompanied infiltration local expansion T CNS Spg15−/− mice. Single-cell analysis revealed an disease-associated microglia (DAM) effector CD8+ prior to neuronal loss. Analysis potential cell–cell communication pathways suggested bidirectional interactions DAM potentially contributing progression summary, shift microglial phenotypes associated with recruitment new characteristic Spg15-driven neuropathology.