학술논문
Astroglial toxicity promotes synaptic degeneration in the thalamocortical circuit in frontotemporal dementia with GRN mutations
Document Type
article
Author
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; Miller, Bruce L; Ullian, Erik M; Krummel, Matthew F; Kriegstein, Arnold; Huang, Eric J
Source
Journal of Clinical Investigation. 133(6)
Subject
Language
Abstract
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.