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ResearchIn-Press PreviewNeuroscience Open Access | 10.1172/JCI164919

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

Elise Marsan,1 Dmitry Velmeshev,2 Arren Ramsey,1 Ravi K. Patel,3 Jiasheng Zhang,1 Mark Koontz,4 Madeline G. Andrews,5 Martina de Majo,4 Cristina Mora,1 Jessica Blumenfeld,6 Alissa N. Li,7 Salvatore Spina,7 Lea T. Grinberg,7 William Seeley,8 Bruce L. Miller,7 Erik M. Ullian,9 Matthew F. Krummel,1 Arnold Kriegstein,7 and Eric J. Huang1

1Department of Pathology, UCSF, San Francisco, United States of America

2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, United States of America

3ImmunoX CoLab, UCSF, San Francisco, United States of America

4Department of Opthalmology, UCSF, San Francisco, United States of America

5School of Biological and Health Systems Engineering, Arizona State University, Tempe, United States of America

6Neuroscience Graduate Program, UCSF, San Francisco, United States of America

7Department of Neurology, UCSF, San Francisco, United States of America

8Sandler Neurosciences Center, UCSF, San Francisco, United States of America

9Department of Ophthalmology, UCSF, San Francisco, United States of America

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1Department of Pathology, UCSF, San Francisco, United States of America

2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, United States of America

3ImmunoX CoLab, UCSF, San Francisco, United States of America

4Department of Opthalmology, UCSF, San Francisco, United States of America

5School of Biological and Health Systems Engineering, Arizona State University, Tempe, United States of America

6Neuroscience Graduate Program, UCSF, San Francisco, United States of America

7Department of Neurology, UCSF, San Francisco, United States of America

8Sandler Neurosciences Center, UCSF, San Francisco, United States of America

9Department of Ophthalmology, UCSF, San Francisco, United States of America

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1Department of Pathology, UCSF, San Francisco, United States of America

2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, United States of America

3ImmunoX CoLab, UCSF, San Francisco, United States of America

4Department of Opthalmology, UCSF, San Francisco, United States of America

5School of Biological and Health Systems Engineering, Arizona State University, Tempe, United States of America

6Neuroscience Graduate Program, UCSF, San Francisco, United States of America

7Department of Neurology, UCSF, San Francisco, United States of America

8Sandler Neurosciences Center, UCSF, San Francisco, United States of America

9Department of Ophthalmology, UCSF, San Francisco, United States of America

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1Department of Pathology, UCSF, San Francisco, United States of America

2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, United States of America

3ImmunoX CoLab, UCSF, San Francisco, United States of America

4Department of Opthalmology, UCSF, San Francisco, United States of America

5School of Biological and Health Systems Engineering, Arizona State University, Tempe, United States of America

6Neuroscience Graduate Program, UCSF, San Francisco, United States of America

7Department of Neurology, UCSF, San Francisco, United States of America

8Sandler Neurosciences Center, UCSF, San Francisco, United States of America

9Department of Ophthalmology, UCSF, San Francisco, United States of America

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1Department of Pathology, UCSF, San Francisco, United States of America

2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, United States of America

3ImmunoX CoLab, UCSF, San Francisco, United States of America

4Department of Opthalmology, UCSF, San Francisco, United States of America

5School of Biological and Health Systems Engineering, Arizona State University, Tempe, United States of America

6Neuroscience Graduate Program, UCSF, San Francisco, United States of America

7Department of Neurology, UCSF, San Francisco, United States of America

8Sandler Neurosciences Center, UCSF, San Francisco, United States of America

9Department of Ophthalmology, UCSF, San Francisco, United States of America

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1Department of Pathology, UCSF, San Francisco, United States of America

2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, United States of America

3ImmunoX CoLab, UCSF, San Francisco, United States of America

4Department of Opthalmology, UCSF, San Francisco, United States of America

5School of Biological and Health Systems Engineering, Arizona State University, Tempe, United States of America

6Neuroscience Graduate Program, UCSF, San Francisco, United States of America

7Department of Neurology, UCSF, San Francisco, United States of America

8Sandler Neurosciences Center, UCSF, San Francisco, United States of America

9Department of Ophthalmology, UCSF, San Francisco, United States of America

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1Department of Pathology, UCSF, San Francisco, United States of America

2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, United States of America

3ImmunoX CoLab, UCSF, San Francisco, United States of America

4Department of Opthalmology, UCSF, San Francisco, United States of America

5School of Biological and Health Systems Engineering, Arizona State University, Tempe, United States of America

6Neuroscience Graduate Program, UCSF, San Francisco, United States of America

7Department of Neurology, UCSF, San Francisco, United States of America

8Sandler Neurosciences Center, UCSF, San Francisco, United States of America

9Department of Ophthalmology, UCSF, San Francisco, United States of America

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1Department of Pathology, UCSF, San Francisco, United States of America

2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, United States of America

3ImmunoX CoLab, UCSF, San Francisco, United States of America

4Department of Opthalmology, UCSF, San Francisco, United States of America

5School of Biological and Health Systems Engineering, Arizona State University, Tempe, United States of America

6Neuroscience Graduate Program, UCSF, San Francisco, United States of America

7Department of Neurology, UCSF, San Francisco, United States of America

8Sandler Neurosciences Center, UCSF, San Francisco, United States of America

9Department of Ophthalmology, UCSF, San Francisco, United States of America

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1Department of Pathology, UCSF, San Francisco, United States of America

2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, United States of America

3ImmunoX CoLab, UCSF, San Francisco, United States of America

4Department of Opthalmology, UCSF, San Francisco, United States of America

5School of Biological and Health Systems Engineering, Arizona State University, Tempe, United States of America

6Neuroscience Graduate Program, UCSF, San Francisco, United States of America

7Department of Neurology, UCSF, San Francisco, United States of America

8Sandler Neurosciences Center, UCSF, San Francisco, United States of America

9Department of Ophthalmology, UCSF, San Francisco, United States of America

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1Department of Pathology, UCSF, San Francisco, United States of America

2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, United States of America

3ImmunoX CoLab, UCSF, San Francisco, United States of America

4Department of Opthalmology, UCSF, San Francisco, United States of America

5School of Biological and Health Systems Engineering, Arizona State University, Tempe, United States of America

6Neuroscience Graduate Program, UCSF, San Francisco, United States of America

7Department of Neurology, UCSF, San Francisco, United States of America

8Sandler Neurosciences Center, UCSF, San Francisco, United States of America

9Department of Ophthalmology, UCSF, San Francisco, United States of America

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1Department of Pathology, UCSF, San Francisco, United States of America

2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, United States of America

3ImmunoX CoLab, UCSF, San Francisco, United States of America

4Department of Opthalmology, UCSF, San Francisco, United States of America

5School of Biological and Health Systems Engineering, Arizona State University, Tempe, United States of America

6Neuroscience Graduate Program, UCSF, San Francisco, United States of America

7Department of Neurology, UCSF, San Francisco, United States of America

8Sandler Neurosciences Center, UCSF, San Francisco, United States of America

9Department of Ophthalmology, UCSF, San Francisco, United States of America

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1Department of Pathology, UCSF, San Francisco, United States of America

2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, United States of America

3ImmunoX CoLab, UCSF, San Francisco, United States of America

4Department of Opthalmology, UCSF, San Francisco, United States of America

5School of Biological and Health Systems Engineering, Arizona State University, Tempe, United States of America

6Neuroscience Graduate Program, UCSF, San Francisco, United States of America

7Department of Neurology, UCSF, San Francisco, United States of America

8Sandler Neurosciences Center, UCSF, San Francisco, United States of America

9Department of Ophthalmology, UCSF, San Francisco, United States of America

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1Department of Pathology, UCSF, San Francisco, United States of America

2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, United States of America

3ImmunoX CoLab, UCSF, San Francisco, United States of America

4Department of Opthalmology, UCSF, San Francisco, United States of America

5School of Biological and Health Systems Engineering, Arizona State University, Tempe, United States of America

6Neuroscience Graduate Program, UCSF, San Francisco, United States of America

7Department of Neurology, UCSF, San Francisco, United States of America

8Sandler Neurosciences Center, UCSF, San Francisco, United States of America

9Department of Ophthalmology, UCSF, San Francisco, United States of America

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1Department of Pathology, UCSF, San Francisco, United States of America

2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, United States of America

3ImmunoX CoLab, UCSF, San Francisco, United States of America

4Department of Opthalmology, UCSF, San Francisco, United States of America

5School of Biological and Health Systems Engineering, Arizona State University, Tempe, United States of America

6Neuroscience Graduate Program, UCSF, San Francisco, United States of America

7Department of Neurology, UCSF, San Francisco, United States of America

8Sandler Neurosciences Center, UCSF, San Francisco, United States of America

9Department of Ophthalmology, UCSF, San Francisco, United States of America

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1Department of Pathology, UCSF, San Francisco, United States of America

2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, United States of America

3ImmunoX CoLab, UCSF, San Francisco, United States of America

4Department of Opthalmology, UCSF, San Francisco, United States of America

5School of Biological and Health Systems Engineering, Arizona State University, Tempe, United States of America

6Neuroscience Graduate Program, UCSF, San Francisco, United States of America

7Department of Neurology, UCSF, San Francisco, United States of America

8Sandler Neurosciences Center, UCSF, San Francisco, United States of America

9Department of Ophthalmology, UCSF, San Francisco, United States of America

Find articles by Miller, B. in: JCI | PubMed | Google Scholar

1Department of Pathology, UCSF, San Francisco, United States of America

2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, United States of America

3ImmunoX CoLab, UCSF, San Francisco, United States of America

4Department of Opthalmology, UCSF, San Francisco, United States of America

5School of Biological and Health Systems Engineering, Arizona State University, Tempe, United States of America

6Neuroscience Graduate Program, UCSF, San Francisco, United States of America

7Department of Neurology, UCSF, San Francisco, United States of America

8Sandler Neurosciences Center, UCSF, San Francisco, United States of America

9Department of Ophthalmology, UCSF, San Francisco, United States of America

Find articles by Ullian, E. in: JCI | PubMed | Google Scholar |

1Department of Pathology, UCSF, San Francisco, United States of America

2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, United States of America

3ImmunoX CoLab, UCSF, San Francisco, United States of America

4Department of Opthalmology, UCSF, San Francisco, United States of America

5School of Biological and Health Systems Engineering, Arizona State University, Tempe, United States of America

6Neuroscience Graduate Program, UCSF, San Francisco, United States of America

7Department of Neurology, UCSF, San Francisco, United States of America

8Sandler Neurosciences Center, UCSF, San Francisco, United States of America

9Department of Ophthalmology, UCSF, San Francisco, United States of America

Find articles by Krummel, M. in: JCI | PubMed | Google Scholar |

1Department of Pathology, UCSF, San Francisco, United States of America

2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, United States of America

3ImmunoX CoLab, UCSF, San Francisco, United States of America

4Department of Opthalmology, UCSF, San Francisco, United States of America

5School of Biological and Health Systems Engineering, Arizona State University, Tempe, United States of America

6Neuroscience Graduate Program, UCSF, San Francisco, United States of America

7Department of Neurology, UCSF, San Francisco, United States of America

8Sandler Neurosciences Center, UCSF, San Francisco, United States of America

9Department of Ophthalmology, UCSF, San Francisco, United States of America

Find articles by Kriegstein, A. in: JCI | PubMed | Google Scholar

1Department of Pathology, UCSF, San Francisco, United States of America

2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, United States of America

3ImmunoX CoLab, UCSF, San Francisco, United States of America

4Department of Opthalmology, UCSF, San Francisco, United States of America

5School of Biological and Health Systems Engineering, Arizona State University, Tempe, United States of America

6Neuroscience Graduate Program, UCSF, San Francisco, United States of America

7Department of Neurology, UCSF, San Francisco, United States of America

8Sandler Neurosciences Center, UCSF, San Francisco, United States of America

9Department of Ophthalmology, UCSF, San Francisco, United States of America

Find articles by Huang, E. in: JCI | PubMed | Google Scholar |

Published January 5, 2023 - More info

J Clin Invest. https://doi.org/10.1172/JCI164919.
Copyright © 2023, Marsan 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/.
Published January 5, 2023 - Version history
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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 previously unappreciated astroglial pathology as a key mechanism in neurodegeneration in FTLD-GRN.

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  • Version 1 (January 5, 2023): In-Press Preview
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