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 4

Transcriptomic and phenotypic characterizations of microglia in patients with FTLD-GRN and 19-month-old Grn–/– mice.

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Transcriptomic and phenotypic characterizations of microglia in patients...
(A) Venn diagrams show the overlap in the DEGs in the microglial (MG) clusters from hTH, hFCX, mTH, and mFCX. Statistics uses hypergeometric tests. (B) Alluvial plot showing the overlap of the GO terms defined by DEGs from the MG clusters in hTH, hFCX, mTH, and mFCX. The width of the band for each GO terms represent its P value calculated based on the cumulative hypergeometric distribution. Blue and red gene names indicate down- and up-regulated DEGs, respectively. (C) Pseudotime analysis of the MG clusters in hTH based on UMAP (left panel), individuals with FTLD-GRN or without (control), or disease duration (right panel). (D) Expression levels of APOE, FTL, and HSPA1A projected onto the UMAP for the MG cluster in hTH. Scale represents log10 of the expression of representative genes. (E–G) Immunostains and confocal images showing the expression of APOE, FTL, and HSPA1A/B in IBA1+ microglia in control and FTLD-GRN cases. (H) Quantification of FTL and HSPA1A/B signal intensity on immunostains. Statistics use 2-tailed Student’s t test, and n represents the number of independent samples tested. All data represent mean ± SEM. *P < 0.05, **P < 0.01. Scale bars: 20μm (immunostains); 10 μm (confocal images).