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 5

Conserved transcriptomic and phenotypic changes in astrocytes in FTLD-GRN and Grn–/– mice.

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Conserved transcriptomic and phenotypic changes in astrocytes in FTLD-GR...
(A) Venn diagrams showing the overlap of DEGs in the astroglial (AST) clusters from hTH, hFCX, mTH and mFCX. Statistics uses hypergeometric tests. (B) DEGs shared by ≥3 AST clusters in mTH, mFCX, hTH and hFCX, with a scale indicating log2 Fold Change that has a cutoff from –0.5 to 0.5. Dot size indicates the log10 Q value for each DEG and color scale indicates log2 Fold Change. Blue and red indicate down- and up-regulated DEGs, respectively. (C) Alluvial plot showing the overlap of GO terms defined by DEGs from AST clusters in hTH, hFCX, mTH, and mFCX. Band width represents P values calculated by accumulative hypergeometric distribution. CMA, chaperone-mediated autophagy; RKT, receptor tyrosine kinases. (D) Pseudotime analysis of AST clusters in hTH based on UMAP (left panel), control versus. FTLD-GRN (middle panel), or disease duration (right panel). (E) Expression of GPC5, SLC1A2, and CLU projected onto UMAP of AST cluster in hTH. (F) Pseudotime analysis of the AST clusters in hFCX based on UMAP (left panel), control versus FTLD-GRN (middle panel), or disease duration (right panel). (G) Expression of SLC1A2 and CLU projected onto UMAP of AST cluster in hFCX. (H–K) Immunohistochemical (top) and confocal images (bottom) of GJA1 (H), AQP4 (I), APOE (J), and EAAT2 (K) in hFCX of control and FTLD-GRN. (L) Quantification of GJA1, CD34, AQP4, and EAAT2 expression on immunostains in control and FTLD-GRN cases. Statistics uses 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, ***P < 0.005. Scale bars: 100μm (immunostains); 20 μm and 30 μm (confocal images).