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
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.
