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

Autor:	Marsan E; Department of Pathology.; ImmunoX Initiative, and., Velmeshev D; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, California, USA.; Department of Neurobiology, Duke University School of Medicine, Durham, North Carolina, USA., Ramsey A; Department of Pathology., Patel RK; ImmunoX Initiative, and., Zhang J; Department of Pathology., Koontz M; Department of Ophthalmology, UCSF, San Francisco, California, USA., Andrews MG; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, California, USA.; School of Biological and Health Systems Engineering, Arizona State University, Tempe, Arizona, USA., de Majo M; Department of Ophthalmology, UCSF, San Francisco, California, USA., Mora C; Department of Pathology., Blumenfeld J; Neuroscience Graduate Program, UCSF, San Francisco, California, USA., Li AN; Memory and Aging Center, Department of Neurology, UCSF, San Francisco, California, USA., Spina S; Memory and Aging Center, Department of Neurology, UCSF, San Francisco, California, USA., Grinberg LT; Department of Pathology.; Memory and Aging Center, Department of Neurology, UCSF, San Francisco, California, USA., Seeley WW; Department of Pathology.; Neuroscience Graduate Program, UCSF, San Francisco, California, USA.; Memory and Aging Center, Department of Neurology, UCSF, San Francisco, California, USA., Miller BL; Memory and Aging Center, Department of Neurology, UCSF, San Francisco, California, USA., Ullian EM; Department of Ophthalmology, UCSF, San Francisco, California, USA.; Neuroscience Graduate Program, UCSF, San Francisco, California, USA., Krummel MF; Department of Pathology.; ImmunoX Initiative, and., Kriegstein AR; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, California, USA.; Neuroscience Graduate Program, UCSF, San Francisco, California, USA., Huang EJ; Department of Pathology.; ImmunoX Initiative, and.; Neuroscience Graduate Program, UCSF, San Francisco, California, USA.; Pathology Service, San Francisco Veterans Health Care System, San Francisco, California, USA.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2023 Mar 15; Vol. 133 (6). Date of Electronic Publication: 2023 Mar 15.
DOI:	10.1172/JCI164919
Abstrakt:	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.
Databáze:	MEDLINE
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