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Cited by 45Amyotrophic Lateral Sclerosis ResearchAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

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

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Marsan, Elise, Velmeshev, Dmitry, Ramsey, Arren, Patel, Ravi K., Zhang, Jiasheng, Koontz, Mark, Andrews, Madeline G., de Majo, Martina +11 more·2023·Journal of Clinical Investigation
DOI 10.1172/jci164919PMC PMC10014110
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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.

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  • Samples were integrated based on SampleID using mnc correct (SnapATAC2) and astrocytes were identified and extracted from each dataset using astrocytic marker genes (SLC1A2, AQP4, ALDH1L1).

    “Samples were iIntegrated based on SampleID using mnc correct (SnapATAC2)90 and astrocytes were identified and extracted from each dataset using astrocytic marker genes (SLC1A2, AQP4, ALDH1L1) as described before91.”

    From APOE genotypes differentially remodel the astrocytic lipid droplet proteome to shape lipid droplet dynamics (2026) · cites this paper as [91]

    The Methods section (“Clustering, differential gene expression, burden score, and nuclei count”; page unavailable) says cell types were annotated using known marker genes, and the Results identify astrocyte clusters. It does not say astrocytes were identified and extracted from each dataset using the specific three-gene set SLC1A2, AQP4, and ALDH1L1. The SnapATAC2 step is attached to citation 90, not this source’s citation 91. (LLM, conf=0.84)

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Sorted by citations

Authors
Marsan, E., Velmeshev, D., Ramsey, A., Patel, R. K., Zhang, J., Koontz, M., Andrews, M. G., de Majo, M., Mora, C., Blumenfeld, J., Li, A. N., Spina, S., Grinberg, L. T., Seeley, W. W., Miller, B. L., Ullian, E. M., Krummel, M. F., Kriegstein, A. R., & Huang, E. J.
Affiliations
  • University of California, San Francisco (US)
  • Duke University (US)
  • San Francisco VA Medical Center (US)
Corresponding author
Huang, Eric J.
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2023-03-15
Volume
133
Issue
6
ISSN
  • 0021-9738 (ISSN-L)
  • 1558-8238
DOI
10.1172/jci164919
PMC
PMC10014110
OpenAlex
W4313545233
Cited by
45
References
11
Citations by year
2026: 10 · 2025: 17 · 2024: 11 · 2023: 7
FWCI
7.33
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Clinical Investigation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • U.S. Department of Veterans Affairs (I01 BX001108)
  • American Federation for Aging Research
  • Glenn Foundation for Medical Research
  • Rainwater Charitable Foundation
  • Fondation pour la Recherche Médicale
  • National Institutes of Health (EY002162, AG019724)
  • University of California, San Francisco (AG019724, P01AG019724)
  • National Institute on Alcohol Abuse and Alcoholism (R01AA027074)
  • National Institute on Aging (U01AG057195, R01AG068290, R01AG057462, U19AG063911, P01AG019724, R01AG081452, K24AG053435, R01AG060477, P30AG062422)
  • National Institute of Mental Health (K99MH121534, R00MH125329)
  • National Eye Institute (P30EY002162)
  • National Institute of Neurological Disorders and Stroke (RF1NS128908, R35NS097305)
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
frontotemporal lobar degeneration, progranulin, GRN mutations, synaptic degeneration, thalamocortical circuits, connexin 43, aquaporin-4, apolipoprotein E, GLT-1, TDP-43 proteinopathy, astrocyte-neuron co-culture, cortical organoids, single-cell transcriptomics, neurodegeneration
MeSH terms
Progranulins, Animals, Astrocytes, Humans, Mutation, Intercellular Signaling Peptides and Proteins, Mice, Frontotemporal Lobar Degeneration, Frontotemporal Dementia

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