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

Autor:	de Majo M; Department of Ophthalmology, University of California San Francisco, San Francisco, CA 94143, USA; Synapticure Inc, Chicago, IL 60612, USA. Electronic address: martina@synapticure.com., Koontz M; Department of Ophthalmology, University of California San Francisco, San Francisco, CA 94143, USA; Synapticure Inc, Chicago, IL 60612, USA., Marsan E; Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA., Salinas N; Department of Ophthalmology, University of California San Francisco, San Francisco, CA 94143, USA., Ramsey A; Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA., Kuo YM; Department of Ophthalmology, University of California San Francisco, San Francisco, CA 94143, USA., Seo K; Department of Ophthalmology, University of California San Francisco, San Francisco, CA 94143, USA., Li H; Department of Ophthalmology, University of California San Francisco, San Francisco, CA 94143, USA., Dräger N; Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA, USA., Leng K; 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., Gonzales SL; Department of Ophthalmology, University of California San Francisco, San Francisco, CA 94143, USA., Kurnellas M; Alector, Inc, South San Francisco, CA 94080, USA., Miyaoka Y; 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., Klim JR; 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., Kampmann M; 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., Ward ME; National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA., Huang EJ; 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., Ullian EM; 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.
Jazyk:	angličtina
Zdroj:	Stem cell reports [Stem Cell Reports] 2023 Mar 14; Vol. 18 (3), pp. 706-719. Date of Electronic Publication: 2023 Feb 23.
DOI:	10.1016/j.stemcr.2023.01.012
Abstrakt:	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. Competing Interests: Conflict of interests M.dM. and M.Koontz are full-time employees and equity holders of Synapticure Inc. E.M.U. is an equity holder of Synapticure Inc. M. Kampmann is an inventor on U.S. Patent 11,254,933 related to CRISPRi and CRISPRa screening, serves on the Scientific Advisory Boards of Engine Biosciences, Casma Therapeutics, Cajal Neuroscience, and Alector, and is an advisor to Modulo Bio and Recursion Therapeutics. J.R.K. is a shareholder of Faze Medicines and QurAlis, and is an author on patent that describes surfaces for the long-term culture of pluripotent cells (U.S. patent 8,648,170) as well as a patent application that describes methods and compositions for restoring STMN2 levels (U.S. patent application 20,220,133,848). M.Kurnellas is a full-time employee and has equity interest in Alector, Inc. N.M.Dräger is a full time employee at Modulo Bio, Inc. All other authors declare no conflict of interest. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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