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ResearchIn-Press PreviewAgingNeuroscience
Open Access | 
10.1172/JCI190035
TGFb signaling promotes astroglial activation and TDP-43 proteinopathy in organoid models of frontotemporal lobar degeneration
Arren C. Ramsey,1 Xiao-Yan Tang,1 Magdalena J. Macias,1 Patricia R. Nano,2 Rufei Lu,1 Brian Benito,1 Cameron M. Lau,1 Jisu Park,1 Jiasheng Zhang,3 Wandy Beatty,4 Tanzila Mukhtar,5 Arnold R. Kriegstein,6 Aparna Bhaduri,7 Elise Marsan,8 and Eric J. Huang1
1Department of Pathology, University of California San Francisco, San Francisco, United States of America
2Department of Biological Chemistry, University of California Los Angeles, Los Angeles, United States of America
3Department of Pathology, Washington University School of Medicine, St. Louis, United States of America
4Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, United States of America
5The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Rese, University of California San Francisco, San Francisco, United States of America
6Department of Neurology, University of California San Francisco, San Francisco, United States of America
7Department of Biological Chemistry, Brain Research Institute UCLA, United States of America
8Center for Alzheimer’s and Related Dementias, National Institutes of Health, Bethesda, United States of America
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1Department of Pathology, University of California San Francisco, San Francisco, United States of America
2Department of Biological Chemistry, University of California Los Angeles, Los Angeles, United States of America
3Department of Pathology, Washington University School of Medicine, St. Louis, United States of America
4Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, United States of America
5The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Rese, University of California San Francisco, San Francisco, United States of America
6Department of Neurology, University of California San Francisco, San Francisco, United States of America
7Department of Biological Chemistry, Brain Research Institute UCLA, United States of America
8Center for Alzheimer’s and Related Dementias, National Institutes of Health, Bethesda, United States of America
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1Department of Pathology, University of California San Francisco, San Francisco, United States of America
2Department of Biological Chemistry, University of California Los Angeles, Los Angeles, United States of America
3Department of Pathology, Washington University School of Medicine, St. Louis, United States of America
4Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, United States of America
5The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Rese, University of California San Francisco, San Francisco, United States of America
6Department of Neurology, University of California San Francisco, San Francisco, United States of America
7Department of Biological Chemistry, Brain Research Institute UCLA, United States of America
8Center for Alzheimer’s and Related Dementias, National Institutes of Health, Bethesda, United States of America
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1Department of Pathology, University of California San Francisco, San Francisco, United States of America
2Department of Biological Chemistry, University of California Los Angeles, Los Angeles, United States of America
3Department of Pathology, Washington University School of Medicine, St. Louis, United States of America
4Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, United States of America
5The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Rese, University of California San Francisco, San Francisco, United States of America
6Department of Neurology, University of California San Francisco, San Francisco, United States of America
7Department of Biological Chemistry, Brain Research Institute UCLA, United States of America
8Center for Alzheimer’s and Related Dementias, National Institutes of Health, Bethesda, United States of America
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1Department of Pathology, University of California San Francisco, San Francisco, United States of America
2Department of Biological Chemistry, University of California Los Angeles, Los Angeles, United States of America
3Department of Pathology, Washington University School of Medicine, St. Louis, United States of America
4Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, United States of America
5The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Rese, University of California San Francisco, San Francisco, United States of America
6Department of Neurology, University of California San Francisco, San Francisco, United States of America
7Department of Biological Chemistry, Brain Research Institute UCLA, United States of America
8Center for Alzheimer’s and Related Dementias, National Institutes of Health, Bethesda, United States of America
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1Department of Pathology, University of California San Francisco, San Francisco, United States of America
2Department of Biological Chemistry, University of California Los Angeles, Los Angeles, United States of America
3Department of Pathology, Washington University School of Medicine, St. Louis, United States of America
4Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, United States of America
5The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Rese, University of California San Francisco, San Francisco, United States of America
6Department of Neurology, University of California San Francisco, San Francisco, United States of America
7Department of Biological Chemistry, Brain Research Institute UCLA, United States of America
8Center for Alzheimer’s and Related Dementias, National Institutes of Health, Bethesda, United States of America
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1Department of Pathology, University of California San Francisco, San Francisco, United States of America
2Department of Biological Chemistry, University of California Los Angeles, Los Angeles, United States of America
3Department of Pathology, Washington University School of Medicine, St. Louis, United States of America
4Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, United States of America
5The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Rese, University of California San Francisco, San Francisco, United States of America
6Department of Neurology, University of California San Francisco, San Francisco, United States of America
7Department of Biological Chemistry, Brain Research Institute UCLA, United States of America
8Center for Alzheimer’s and Related Dementias, National Institutes of Health, Bethesda, United States of America
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1Department of Pathology, University of California San Francisco, San Francisco, United States of America
2Department of Biological Chemistry, University of California Los Angeles, Los Angeles, United States of America
3Department of Pathology, Washington University School of Medicine, St. Louis, United States of America
4Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, United States of America
5The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Rese, University of California San Francisco, San Francisco, United States of America
6Department of Neurology, University of California San Francisco, San Francisco, United States of America
7Department of Biological Chemistry, Brain Research Institute UCLA, United States of America
8Center for Alzheimer’s and Related Dementias, National Institutes of Health, Bethesda, United States of America
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1Department of Pathology, University of California San Francisco, San Francisco, United States of America
2Department of Biological Chemistry, University of California Los Angeles, Los Angeles, United States of America
3Department of Pathology, Washington University School of Medicine, St. Louis, United States of America
4Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, United States of America
5The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Rese, University of California San Francisco, San Francisco, United States of America
6Department of Neurology, University of California San Francisco, San Francisco, United States of America
7Department of Biological Chemistry, Brain Research Institute UCLA, United States of America
8Center for Alzheimer’s and Related Dementias, National Institutes of Health, Bethesda, United States of America
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1Department of Pathology, University of California San Francisco, San Francisco, United States of America
2Department of Biological Chemistry, University of California Los Angeles, Los Angeles, United States of America
3Department of Pathology, Washington University School of Medicine, St. Louis, United States of America
4Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, United States of America
5The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Rese, University of California San Francisco, San Francisco, United States of America
6Department of Neurology, University of California San Francisco, San Francisco, United States of America
7Department of Biological Chemistry, Brain Research Institute UCLA, United States of America
8Center for Alzheimer’s and Related Dementias, National Institutes of Health, Bethesda, United States of America
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1Department of Pathology, University of California San Francisco, San Francisco, United States of America
2Department of Biological Chemistry, University of California Los Angeles, Los Angeles, United States of America
3Department of Pathology, Washington University School of Medicine, St. Louis, United States of America
4Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, United States of America
5The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Rese, University of California San Francisco, San Francisco, United States of America
6Department of Neurology, University of California San Francisco, San Francisco, United States of America
7Department of Biological Chemistry, Brain Research Institute UCLA, United States of America
8Center for Alzheimer’s and Related Dementias, National Institutes of Health, Bethesda, United States of America
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1Department of Pathology, University of California San Francisco, San Francisco, United States of America
2Department of Biological Chemistry, University of California Los Angeles, Los Angeles, United States of America
3Department of Pathology, Washington University School of Medicine, St. Louis, United States of America
4Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, United States of America
5The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Rese, University of California San Francisco, San Francisco, United States of America
6Department of Neurology, University of California San Francisco, San Francisco, United States of America
7Department of Biological Chemistry, Brain Research Institute UCLA, United States of America
8Center for Alzheimer’s and Related Dementias, National Institutes of Health, Bethesda, United States of America
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1Department of Pathology, University of California San Francisco, San Francisco, United States of America
2Department of Biological Chemistry, University of California Los Angeles, Los Angeles, United States of America
3Department of Pathology, Washington University School of Medicine, St. Louis, United States of America
4Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, United States of America
5The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Rese, University of California San Francisco, San Francisco, United States of America
6Department of Neurology, University of California San Francisco, San Francisco, United States of America
7Department of Biological Chemistry, Brain Research Institute UCLA, United States of America
8Center for Alzheimer’s and Related Dementias, National Institutes of Health, Bethesda, United States of America
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1Department of Pathology, University of California San Francisco, San Francisco, United States of America
2Department of Biological Chemistry, University of California Los Angeles, Los Angeles, United States of America
3Department of Pathology, Washington University School of Medicine, St. Louis, United States of America
4Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, United States of America
5The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Rese, University of California San Francisco, San Francisco, United States of America
6Department of Neurology, University of California San Francisco, San Francisco, United States of America
7Department of Biological Chemistry, Brain Research Institute UCLA, United States of America
8Center for Alzheimer’s and Related Dementias, National Institutes of Health, Bethesda, United States of America
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1Department of Pathology, University of California San Francisco, San Francisco, United States of America
2Department of Biological Chemistry, University of California Los Angeles, Los Angeles, United States of America
3Department of Pathology, Washington University School of Medicine, St. Louis, United States of America
4Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, United States of America
5The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Rese, University of California San Francisco, San Francisco, United States of America
6Department of Neurology, University of California San Francisco, San Francisco, United States of America
7Department of Biological Chemistry, Brain Research Institute UCLA, United States of America
8Center for Alzheimer’s and Related Dementias, National Institutes of Health, Bethesda, United States of America
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Published June 16, 2026 - More info
Copyright © 2026, Ramsey et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)