Astroglial toxicity promotes synaptic degeneration in the thalamocortical circuit in frontotemporal dementia with GRN mutations

• Published in: The Journal of clinical investigation Vol. 133; no. 6; pp. 1 - 18
• Main Authors: Marsan, Elise, Velmeshev, Dmitry, Ramsey, Arren, Patel, Ravi K., Zhang, Jiasheng, Koontz, Mark, Andrews, Madeline G., de Majo, Martina, Mora, Cristina, Blumenfeld, Jessica, Li, Alissa N., Spina, Salvatore, Grinberg, Lea T., Seeley, William W., Miller, Bruce L., Ullian, Erik M., Krummel, Matthew F., Kriegstein, Arnold R., Huang, Eric J.
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 15.03.2023
• Subjects: Animals; Apolipoprotein E; Aquaporin 4; Astrocytes; Astrocytes - metabolism; Biomedical research; Brain; Connexin 43; Cortex (frontal); Dementia; Dementia disorders; Diagnosis; DNA testing; Frontotemporal dementia; Frontotemporal Dementia - genetics; Frontotemporal Lobar Degeneration - genetics; Frontotemporal Lobar Degeneration - metabolism; Frontotemporal Lobar Degeneration - pathology; Gap junctions; Gene mutations; Genes; Genetic aspects; Glutamic acid transporter; Health aspects; Humans; Intercellular Signaling Peptides and Proteins - genetics; Lipid-binding protein; Mice; Mutation; Neurodegeneration; Neurons; Neuropathology; Neuroscience; Organoids; Pathology; Pluripotency; Progranulins - genetics; Proteins; Thalamus; Toxicity; Transcriptomics; United States; Molecular pathology; Neuroscience; Neurodegeneration; Dementia
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI164919

Mutations in the human progranulin (GRN) gene are a leading cause of frontotemporal lobar degeneration (FTLD). While previous studies implicate aberrant microglial activation as a disease-driving factor in neurodegeneration in the thalamocortical circuit in Grn-/- mice, the exact mechanism for neurodegeneration in FTLD-GRN remains unclear. By performing comparative single-cell transcriptomics in the thalamus and frontal cortex of Grn-/- mice and patients with FTLD-GRN, we have uncovered a highly conserved astroglial pathology characterized by upregulation of gap junction protein GJA1, water channel AQP4, and lipid-binding protein APOE, and downregulation of glutamate transporter SLC1A2 that promoted profound synaptic degeneration across the two species. This astroglial toxicity could be recapitulated in mouse astrocyte-neuron cocultures and by transplanting induced pluripotent stem cell-derived astrocytes to cortical organoids, where progranulin-deficient astrocytes promoted synaptic degeneration, neuronal stress, and TDP-43 proteinopathy. Together, these results reveal a previously unappreciated astroglial pathology as a potential key mechanism in neurodegeneration in FTLD-GRN.