TGF-β signaling promotes astroglial activation and TDP-43 proteinopathy in organoid models of frontotemporal lobar degeneration
Arren C. Ramsey, Xiao-Yan Tang, Magdalena J. Macias, Patricia R. Nano, Rufei Lu, Brian Benito, Cameron M. Lau, Jisu Park, Jiasheng Zhang, Wandy Beatty, Tanzila Mukhtar, Arnold R. Kriegstein, Aparna Bhaduri, Elise Marsan, Eric J. Huang
Arren C. Ramsey, Xiao-Yan Tang, Magdalena J. Macias, Patricia R. Nano, Rufei Lu, Brian Benito, Cameron M. Lau, Jisu Park, Jiasheng Zhang, Wandy Beatty, Tanzila Mukhtar, Arnold R. Kriegstein, Aparna Bhaduri, Elise Marsan, Eric J. Huang
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Research Article Aging Neuroscience

TGF-β signaling promotes astroglial activation and TDP-43 proteinopathy in organoid models of frontotemporal lobar degeneration

Abstract

Dominant mutations in progranulin (GRN) gene cause frontotemporal lobar degeneration (FTLD-GRN), whereas homozygous GRN mutations lead to neuronal ceroid lipofuscinosis, a childhood neurodegenerative disorder. While recent transcriptomic studies reveal profound glial and neuronal pathology in FTLD-GRN at the disease end stage, the mechanism that disrupts glia-neuron homeostasis remains unclear. Using induced pluripotent stem cell–derived cortical organoids, we showed that GRN–/– and GRNR493X mutations led to precocious astrogliosis that promoted neuronal stress and synaptic loss. Single-cell transcriptomics and histopathology analyses revealed a robust activation in the TGF-β signaling pathway in GRN–/– and GRNR493X/R493X astrocytes, which was accompanied by features of immune activation, loss of synaptic support, and abundant pTDP-43+ fibrils in astroglial cytoplasm, a feature characteristic of FTLD-GRN. Intriguingly, blocking TGF-β signaling mitigated astroglial activation and pTDP-43 proteinopathy in GRN–/– organoids. Together, these results provide insights into the cell-autonomous role of astroglial activation in neurodegeneration caused by progranulin deficiency.

Authors

Arren C. Ramsey, Xiao-Yan Tang, Magdalena J. Macias, Patricia R. Nano, Rufei Lu, Brian Benito, Cameron M. Lau, Jisu Park, Jiasheng Zhang, Wandy Beatty, Tanzila Mukhtar, Arnold R. Kriegstein, Aparna Bhaduri, Elise Marsan, Eric J. Huang

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Figure 7

Precocious neurogenesis and astrogliogenesis in GRNR493X/R493X cortical organoids.

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Precocious neurogenesis and astrogliogenesis in GRNR493X/R493X cortical ...
(A) Confocal images of CTIP2, SATB2, and DAPI in GRN+/+, GRNR493X/+, and GRNR493X/R493X cortical organoids at 5, 10, and 15 weeks. (B–D) Quantification of the number of CTIP2+SATB2– L5–6 cortical neurons (B), CTIP2–SATB2+ L1–4 cortical neurons (C), and CTIP2+SATB2+ transitioning cortical neurons (D) at different time points in GRN+/+ (blue circle), GRNR493X/+ (red triangle), and GRNR493X/R493X (red square) cortical organoids at 5, 10, and 15 weeks. Organoids (n = 9) from 3 independent biological replicate experiments were analyzed per time point per genotype. (E) Confocal images of NESTIN, SOX9, GFAP, and S100b in GRN+/+, GRNR493X/+ and GRNR493X/R493X cortical organoids at 10, 16, and 25 weeks. (F–H) Quantification of the number of NES+SOX9+S100b– astroglial progenitors (F), NES+SOX9+S100b+ differentiating astrocytes (G), and NES–SOX9+S100b+ mature astrocytes (H) at different time points in GRN+/+ (blue circle), GRNR493X/+ (red triangle), and GRNR493X/R493X (red square) cortical organoids at 10, 16, and 25 weeks. Organoids (n = 9) from 3 independent biological replicate experiments were analyzed per time point per genotype. Statistics used Student’s t test. All data represent mean ± SEM.