Astroglial toxicity promotes synaptic degeneration in the thalamocortical circuit in frontotemporal dementia with GRN mutations
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
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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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 6

Neuronal phenotypes in patients with FTLD-GRN and Grn–/– mice.

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Neuronal phenotypes in patients with FTLD-GRN and Grn–/– mice. (A) Heatm...
(A) Heatmaps showing the top 4 GO terms shared by the neuronal clusters in hTH, hFCX, mTH, and mFCX. Statistics use hypergeometric tests. (B) Volcano plots showing DEGs in neuronal clusters in hTH and hFCX and genes related to the GO terms in A. (C and D) Bar graphs showing the number of DEGs in the neuronal clusters in patients with FTLD-GRN and Grn–/– mice that overlap with TDP-43-mediated misspliced genes. (E and F) Immunostains for GAD1 and MAP2 in hTH (E) and for MAP2 and NRGN in hFCX (F) in control and FTLD-GRN cases. Scale bars: 300 μm (E, top); 200 μm (F, top); 20 μm (E and F, bottom) (G) Quantifications of GAD1+ and MAP2+ cells in hTH, and MAP2+ and NRGN+ cells in hFCX in control and FTLD-GRN cases. (H) Confocal and IMARIS images of PSD-95+, SYP+, and PSD-95+/SYP+ synapses near MAP2+ neurons in hFCX of control and FTLD-GRN patients. Scale bars: 7 μm (top); 4 μm (middle and bottom). (I) Quantification of PSD-95+ or SYP+ area in MAP2+ neurons in control and FTLD-GRN cases. (J) Confocal and IMARIS images of PSD-95+ in GFAP+ processes and cell bodies in L2/3 of hFCX in control and FTLD-GRN cases. Scale bars: 20 μm (top); 10 μm (middle and bottom). (K) Quantification of PSD-95+ area in GFAP+ or IBA1+ cells in control and FTLD-GRN cases. (L) Confocal and IMARIS images showing colocalization of PSD-95+ and LAMP1+ vesicles in GFAP+ astrocytes in hFCX of control and FTLD-GRN cases. Scale bars: 10 μm. (M and N) Confocal and IMARIS images of NF68, IBA1, and GFAP (M) and TDP-43 and GFAP (N) in hFCX of control and FTLD-GRN cases. Scale bars: 10 μm. All data represent mean ± SEM. Statistics in G, I, and K uses 2-tailed student’s t test, and n represents the number of independent samples tested. *P < 0.05, **P < 0.01, ***P < 0.005, ****P < 0.0001.