Granulin loss of function in human mature brain organoids implicates astrocytes in TDP-43 pathology

Martina de Majo; Mark Koontz; Elise Marsan; Nir Salinas; Arren Ramsey; Yien-Ming Kuo; Kyounghee Seo; Huinan Li; Nina Dräger; Kun Leng; Santiago L Gonzales; Michael Kurnellas; Yuichiro Miyaoka; Joseph R Klim; Martin Kampmann; Michael E Ward; Eric J Huang; Erik M Ullian

doi:10.1016/j.stemcr.2023.01.012

Granulin loss of function in human mature brain organoids implicates astrocytes in TDP-43 pathology

Stem Cell Reports. 2023 Mar 14;18(3):706-719. doi: 10.1016/j.stemcr.2023.01.012. Epub 2023 Feb 23.

Authors

Martina de Majo¹, Mark Koontz², Elise Marsan³, Nir Salinas⁴, Arren Ramsey³, Yien-Ming Kuo⁴, Kyounghee Seo⁴, Huinan Li⁴, Nina Dräger⁵, Kun Leng⁶, Santiago L Gonzales⁴, Michael Kurnellas⁷, Yuichiro Miyaoka⁸, Joseph R Klim⁹, Martin Kampmann¹⁰, Michael E Ward¹¹, Eric J Huang¹², Erik M Ullian¹³

Affiliations

¹ Department of Ophthalmology, University of California San Francisco, San Francisco, CA 94143, USA; Synapticure Inc, Chicago, IL 60612, USA. Electronic address: martina@synapticure.com.
² Department of Ophthalmology, University of California San Francisco, San Francisco, CA 94143, USA; Synapticure Inc, Chicago, IL 60612, USA.
³ Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA.
⁴ Department of Ophthalmology, University of California San Francisco, San Francisco, CA 94143, USA.
⁵ Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA, USA.
⁶ Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA, USA; Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA, USA.
⁷ Alector, Inc, South San Francisco, CA 94080, USA.
⁸ Regenerative Medicine Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya, Tokyo 156-8506, Japan; Gladstone Institutes, San Francisco, CA 94158, USA.
⁹ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
¹⁰ Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
¹¹ National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
¹² Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA; Neuroscience Graduate Program, University of California San Francisco, San Francisco, CA 94158, USA.
¹³ Department of Ophthalmology, University of California San Francisco, San Francisco, CA 94143, USA; Neuroscience Graduate Program, University of California San Francisco, San Francisco, CA 94158, USA. Electronic address: erik.ullian@ucsf.edu.

Abstract

Loss of function (LoF) of TAR-DNA binding protein 43 (TDP-43) and mis-localization, together with TDP-43-positive and hyperphosphorylated inclusions, are found in post-mortem tissue of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients, including those carrying LoF variants in the progranulin gene (GRN). Modeling TDP-43 pathology has been challenging in vivo and in vitro. We present a three-dimensional induced pluripotent stem cell (iPSC)-derived paradigm-mature brain organoids (mbOrg)-composed of cortical-like-astrocytes (iA) and neurons. When devoid of GRN, mbOrgs spontaneously recapitulate TDP-43 mis-localization, hyperphosphorylation, and LoF phenotypes. Mixing and matching genotypes in mbOrgs showed that GRN^-/- iA are drivers for TDP-43 pathology. Finally, we rescued TDP-43 LoF by adding exogenous progranulin, demonstrating a link between TDP-43 LoF and progranulin expression. In conclusion, we present an iPSC-derived platform that shows striking features of human TDP-43 proteinopathy and provides a tool for the mechanistic modeling of TDP-43 pathology and patient-tailored therapeutic screening for FTD and ALS.

Keywords: ALS; FTD; astrocytes; iPSC; neurodegeneration; neurons; strocyte-neuronal signaling.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Amyotrophic Lateral Sclerosis* / pathology
Astrocytes / metabolism
Brain / metabolism
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Frontotemporal Dementia* / genetics
Granulins / genetics
Granulins / metabolism
Humans
Mutation
Progranulins / genetics
Progranulins / metabolism

Substances

Granulins
Progranulins
DNA-Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding