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Updated: Jul 6, 2025
Author Spotlight: Deciphering the Role of ATM in Ataxia-Telangiectasia and the Associated Cerebellar Degeneration
Published on: December 27, 2024
ATM-deficiency-induced microglial activation promotes neurodegeneration in ataxia-telangiectasia
Jenny Lai1, Didem Demirbas2, Junho Kim2
1Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA; The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Program in Neuroscience, Harvard University, Boston, MA 02115, USA.
Abstract:
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.
Insights
Ataxia-telangiectasia (A-T) involves microglial inflammation in the cerebellum. Activated A-T microglia promote neuroinflammation and neuronal death, suggesting a key role in A-T neurodegeneration.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Ataxia-telangiectasia (A-T) is caused by ATM loss-of-function, but the mechanisms of cerebellar neurodegeneration are not fully understood.
- ATM is highly expressed in microglia, suggesting a potential role for these immune cells in A-T pathogenesis.
Purpose of the Study:
- To investigate the role of microglia in the selective degeneration of cerebellar neurons in A-T.
- To elucidate the molecular mechanisms underlying microglial activation and neurotoxicity in A-T.
Main Methods:
- Single-nucleus RNA sequencing of human A-T patient cerebellum samples.
- Pseudotime analysis to infer microglial activation dynamics.
- Transcriptomic profiling of A-T induced pluripotent stem cell (iPSC)-derived microglia.
- Co-culture experiments with A-T iPSC-derived neurons and microglia.
Main Results:
- Evidence of microglial inflammation in the cerebellum of A-T patients.
- A-T microglia activation precedes neuronal apoptosis and involves increased neurotoxic cytokine signaling.
- A-T microglia exhibit cell-intrinsic activation of cytokine production and innate immune pathways.
- A-T microglia induce cytotoxicity in co-cultured neurons.
Conclusions:
- Cell-intrinsic microglial activation is implicated in promoting neurodegeneration in A-T.
- Microglial inflammation and neurotoxic signaling represent a potential therapeutic target for A-T.
