Astroglial toxicity promotes synaptic degeneration in the thalamocortical circuit in frontotemporal dementia with GRN mutations
Elise Marsan, … , Arnold R. Kriegstein, Eric J. Huang
Elise Marsan, … , Arnold R. Kriegstein, Eric J. Huang
Published January 5, 2023
Citation Information: J Clin Invest. 2023;133(6):e164919. https://doi.org/10.1172/JCI164919.
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Research Article Neuroscience

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

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.

Authors

Elise Marsan, Dmitry Velmeshev, Arren Ramsey, Ravi K. Patel, Jiasheng Zhang, Mark Koontz, Madeline G. Andrews, Martina de Majo, Cristina Mora, Jessica Blumenfeld, Alissa N. Li, Salvatore Spina, Lea T. Grinberg, William W. Seeley, Bruce L. Miller, Erik M. Ullian, Matthew F. Krummel, Arnold R. Kriegstein, Eric J. Huang

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Figure 8

iPSC-derived PGRN-deficient astrocytes fail to promote synaptic refinement, but enhance neuronal stress and TDP-43 proteinopathy in cortical organoids.

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iPSC-derived PGRN-deficient astrocytes fail to promote synaptic refineme...
(A) Schematic diagram for transplanting GRN+/+ and GRN–/– iPSC-derived astrocytes (iAST) to organoids. (B) Confocal images of GFP+ GRN+/+ iAST and GRN–/– iAST in organoids 1-week after transplantation. Scale bars: 500 μm. (C) Confocal and IMARIS images of GFP, PSD-95, and Bassoon in GRN+/+ iAST and GRN–/– iAST within the organoids. Scale bars: 10 μm and 3 μm (inset and IMARIS). (D) Quantification of PSD-95 puncta size outside and inside GFP+ area in organoids transplanted with GRN+/+ iAST (n = 10), GRN–/– iAST (n = 9), or no iAST (n = 4). Statistics use 1-way ANOVA (upper panel) and 2-tailed Student’s t test (lower panel). (E) Confocal and IMARIS images of GFP and GJA1 in GRN+/+ iAST and GRN–/– iAST in organoids. Scale bars: 20 μm. (F) Quantification of GJA1+ surface area in organoids with GRN+/+ iAST (n = 10) or GRN–/– iAST (n = 9), Statistics use 2-tailed Student’s t test. (G) Confocal and IMARIS images of GFP and EAAT2 in GRN+/+ iAST and GRN–/– iAST in organoids. Scale bars: 20 μm. (H) Quantification of EAAT2+ area in GFP+ GRN+/+ iAST (n = 10) and GFP+ GRN–/– iAST (n = 9). Statistics use 2-tailed Student’s t test. (I) Confocal images of GFP and PGK1 in organoids transplanted with GRN+/+ or GRN–/– iASTs. Scale bars: 20 μm. (J) Quantification of PGK1+ area in MAP2+ neurons in organoids transplanted with GRN+/+ iASTs (n = 12) or GRN–/– iAST (n = 10). Statistics use 2-tailed Student’s t test. (K) Confocal and IMARIS images of TDP-43 and NeuN in GRN+/+ iAST and GRN–/– iAST-containing organoids. Scale bars: 10 μm and 5 μm (inset and IMARIS) (L) Quantification of TDP-43+ signals in extranuclear (enTDP-43) area (top) and particle size (bottom) in organoids transplanted with GRN+/+ iAST (n = 11), GRN–/– iAST (n = 10), or no iAST (n = 4). 1-way ANOVA. All quantification data represent mean ± SEM, and n represents the number of independent samples tested. *P < 0.05, **P < 0.01.