ATM-deficiency-induced microglial activation promotes neurodegeneration in ataxia-telangiectasia

• Published in: Cell reports (Cambridge) 2024-01, Vol.43 (1), p.113622, Article 113622
• Main Authors: Lai, Jenny, Demirbas, Didem, Kim, Junho, Jeffries, Ailsa M., Tolles, Allie, Park, Junseok, Chittenden, Thomas W., Buckley, Patrick G., Yu, Timothy W., Lodato, Michael A., Lee, Eunjung Alice
• Format: Article
• Language: English
• Subjects: ataxia-telangiectasia; cerebellar degeneration; CP: Neuroscience; microglial activation; single-nucleus RNA-sequencing
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113622

While ATM loss of function has long been identified as the genetic cause of ataxia-telangiectasia (A-T), how it leads to selective and progressive degeneration of cerebellar Purkinje and granule neurons remains unclear. ATM expression is enriched in microglia throughout cerebellar development and adulthood. Here, we find evidence of microglial inflammation in the cerebellum of patients with A-T using single-nucleus RNA sequencing. Pseudotime analysis revealed that activation of A-T microglia preceded upregulation of apoptosis-related genes in granule and Purkinje neurons and that microglia exhibited increased neurotoxic cytokine signaling to granule and Purkinje neurons in A-T. To confirm these findings experimentally, we performed transcriptomic profiling of A-T induced pluripotent stem cell (iPSC)-derived microglia, which revealed cell-intrinsic microglial activation of cytokine production and innate immune response pathways compared to controls. Furthermore, A-T microglia co-culture with either control or A-T iPSC-derived neurons was sufficient to induce cytotoxicity. Taken together, these studies reveal that cell-intrinsic microglial activation may promote neurodegeneration in A-T. [Display omitted] •A-T microglia show signatures of aging and disease-associated microglia•A-T cerebellum has greater microglia activation compared to cortex•A-T patient iPSC-derived microglia (iMGLs) exhibit cell-intrinsic activation•A-T iMGLs are sufficient to increase cytotoxicity of neuronal co-cultures Lai et al. characterize cell-type-specific transcriptional changes in ataxia-telangiectasia (A-T) using single-nucleus RNA sequencing of patient brain tissue and find that cell-intrinsic activation of microglia in A-T promotes cytotoxicity. These findings provide mechanistic insight into the role of microglia on cerebellar degeneration in A-T.