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Granulin loss of function in human mature brain organoids implicates astrocytes in TDP-43 pathology.
de Majo, Martina; Koontz, Mark; Marsan, Elise; Salinas, Nir; Ramsey, Arren; Kuo, Yien-Ming; Seo, Kyounghee; Li, Huinan; Dräger, Nina; Leng, Kun; Gonzales, Santiago L; Kurnellas, Michael; Miyaoka, Yuichiro; Klim, Joseph R; Kampmann, Martin; Ward, Michael E; Huang, Eric J; Ullian, Erik M.
Afiliação
  • 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.
Stem Cell Reports ; 18(3): 706-719, 2023 03 14.
Article em En | MEDLINE | ID: mdl-36827976
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Demência Frontotemporal / Esclerose Lateral Amiotrófica Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article
Texto completo
Imprimir
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PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Demência Frontotemporal / Esclerose Lateral Amiotrófica Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article