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 1

Glial pathology in thalamus and frontal cortex of patients with FTLD-GRN and Grn–/– mice.

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Glial pathology in thalamus and frontal cortex of patients with FTLD-GRN...
(A and B) Immunostains for IBA1 and GFAP in the thalamus (hTH) and frontal cortex (hFCX) in control and FTLD-GRN cases. (C and D) Quantification of IBA1+ microglia and GFAP+ astrocyte density in hTH and hFCX (C) and mFCX and mTH (D). Statistics for IBA1+ microglia in hTH, hFCX, mTH, and mFCX use parametric 2-tailed Student’s t test and for GFAP+ astrocytes parametric (for hFCX, mTH, and mFCX) or nonparametric 2-tailed Student’s t test (for hTH). (E and F) Volcano plots showing DEGs in hTH (E) and hFCX (F) from the Nanostring nCounter neuropathology and neuroinflammation panels. (G) Heatmap showing nCounter pathway scores in hTH and hFCX of patients with FTLD-GRN. L1/2 indicates the border between layers 1 and 2 of the frontal cortex. All data represent mean ± SEM, and n represents the number of independent human and mouse samples used. *P < 0.05, **P < 0.01 ***P < 0.001, ****P < 0.0001. Scale bars: 100 μm; 20 μm (inset).