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

Jenny Lai; Didem Demirbas; Junho Kim; Ailsa M. Jeffries; Allie Tolles; Junseok Park; Thomas W. Chittenden; Patrick G. Buckley; Timothy W. Yu; Michael A. Lodato; Eunjung Alice Lee

Cell Reports (Jan 2024)

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

Jenny Lai,
Didem Demirbas,
Junho Kim,
Ailsa M. Jeffries,
Allie Tolles,
Junseok Park,
Thomas W. Chittenden,
Patrick G. Buckley,
Timothy W. Yu,
Michael A. Lodato,
Eunjung Alice Lee

Affiliations

Jenny Lai: Division 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
Didem Demirbas: Division 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
Junho Kim: Division 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
Ailsa M. Jeffries: Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Allie Tolles: Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Junseok Park: Division 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
Thomas W. Chittenden: Division of Genetics and Genomics, Department of Pediatrics, Boston Children’s Hospital, Boston, MA 02115, USA; Computational Statistics and Bioinformatics Group, Genuity AI Research Institute, Genuity Science, Boston, MA 02114, USA
Patrick G. Buckley: Genuity Genomics Centre, Genuity Science, D18 K7W4 Dublin, Ireland
Timothy W. Yu: Division 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
Michael A. Lodato: Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA; Corresponding author
Eunjung Alice Lee: Division 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; Corresponding author

Journal volume & issue: Vol. 43, no. 1
p. 113622

Abstract

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Summary: 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.

CP: Neuroscience

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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