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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\u2013derived cells, we identified microgliosis accompanied by infiltration and local expansion of T cells in the CNS of Spg15\u2212\/\u2212 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\u2013cell communication pathways suggested bidirectional interactions between DAM and effector CD8+ T cells, potentially contributing to disease progression in Spg15\u2212\/\u2212 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.<\/jats:p>","DOI":"10.1084\/jem.20232357","type":"journal-article","created":{"date-parts":[[2025,3,20]],"date-time":"2025-03-20T02:20:46Z","timestamp":1742437246000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":11,"title":["Microglia and CD8+ T cell activation precede neuronal loss in a murine model of spastic paraplegia 15"],"prefix":"10.1084","volume":"222","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4406-1206","authenticated-orcid":true,"given":"Aleksej","family":"Frolov","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043j0f473","id-type":"ROR","asserted-by":"publisher"}],"name":"Deutsches Zentrum f\u00fcr Neurodegenerative Erkrankungen (DZNE) 1 Immunogenomics and Neurodegeneration, , 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