Astroglial toxicity promotes synaptic degeneration in the thalamocortical circuit in frontotemporal dementia with GRN mutations
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:133 |
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| Enthalten in: |
The Journal of clinical investigation - 133(2023), 6 vom: 15. März |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Marsan, Elise [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 16.03.2023 Date Revised 02.02.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1172/JCI164919 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM351140247 |
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| 100 | 1 | |a Marsan, Elise |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Astroglial toxicity promotes synaptic degeneration in the thalamocortical circuit in frontotemporal dementia with GRN mutations |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 16.03.2023 | ||
| 500 | |a Date Revised 02.02.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a Dementia | |
| 650 | 4 | |a Molecular pathology | |
| 650 | 4 | |a Neurodegeneration | |
| 650 | 4 | |a Neuroscience | |
| 650 | 7 | |a Progranulins |2 NLM | |
| 650 | 7 | |a Intercellular Signaling Peptides and Proteins |2 NLM | |
| 650 | 7 | |a GRN protein, human |2 NLM | |
| 650 | 7 | |a Grn protein, mouse |2 NLM | |
| 700 | 1 | |a Velmeshev, Dmitry |e verfasserin |4 aut | |
| 700 | 1 | |a Ramsey, Arren |e verfasserin |4 aut | |
| 700 | 1 | |a Patel, Ravi K |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Jiasheng |e verfasserin |4 aut | |
| 700 | 1 | |a Koontz, Mark |e verfasserin |4 aut | |
| 700 | 1 | |a Andrews, Madeline G |e verfasserin |4 aut | |
| 700 | 1 | |a de Majo, Martina |e verfasserin |4 aut | |
| 700 | 1 | |a Mora, Cristina |e verfasserin |4 aut | |
| 700 | 1 | |a Blumenfeld, Jessica |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Alissa N |e verfasserin |4 aut | |
| 700 | 1 | |a Spina, Salvatore |e verfasserin |4 aut | |
| 700 | 1 | |a Grinberg, Lea T |e verfasserin |4 aut | |
| 700 | 1 | |a Seeley, William W |e verfasserin |4 aut | |
| 700 | 1 | |a Miller, Bruce L |e verfasserin |4 aut | |
| 700 | 1 | |a Ullian, Erik M |e verfasserin |4 aut | |
| 700 | 1 | |a Krummel, Matthew F |e verfasserin |4 aut | |
| 700 | 1 | |a Kriegstein, Arnold R |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Eric J |e verfasserin |4 aut | |
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