Human tau mutations in cerebral organoids induce a progressive dyshomeostasis of cholesterol.

Autor:	Glasauer SMK; Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA., Goderie SK; Neural Stem Cell Institute, Rensselaer, NY 12144, USA., Rauch JN; Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA., Guzman E; Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA., Audouard M; Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA., Bertucci T; Neural Stem Cell Institute, Rensselaer, NY 12144, USA., Joy S; Neural Stem Cell Institute, Rensselaer, NY 12144, USA., Rommelfanger E; Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA., Luna G; Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA., Keane-Rivera E; Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA., Lotz S; Neural Stem Cell Institute, Rensselaer, NY 12144, USA., Borden S; Neural Stem Cell Institute, Rensselaer, NY 12144, USA., Armando AM; Department of Pharmacology, University of California, San Diego, San Diego, CA 92093, USA., Quehenberger O; Department of Pharmacology, University of California, San Diego, San Diego, CA 92093, USA., Temple S; Neural Stem Cell Institute, Rensselaer, NY 12144, USA. Electronic address: sallytemple@neuralsci.org., Kosik KS; Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA. Electronic address: kosik@lifesci.ucsb.edu.
Jazyk:	angličtina
Zdroj:	Stem cell reports [Stem Cell Reports] 2022 Sep 13; Vol. 17 (9), pp. 2127-2140. Date of Electronic Publication: 2022 Aug 18.
DOI:	10.1016/j.stemcr.2022.07.011
Abstrakt:	Mutations in the MAPT gene that encodes tau lead to frontotemporal dementia (FTD) with pathology evident in both cerebral neurons and glia. Human cerebral organoids (hCOs) from individuals harboring pathogenic tau mutations can reveal the earliest downstream effects on molecular pathways within a developmental context, generating interacting neurons and glia. We found that in hCOs carrying the V337M and R406W tau mutations, the cholesterol biosynthesis pathway in astrocytes was the top upregulated gene set compared with isogenic controls by single-cell RNA sequencing (scRNA-seq). The 15 upregulated genes included HMGCR, ACAT2, STARD4, LDLR, and SREBF2. This result was confirmed in a homozygous R406W mutant cell line by immunostaining and sterol measurements. Cholesterol abundance in the brain is tightly regulated by efflux and cholesterol biosynthetic enzyme levels in astrocytes, and dysregulation can cause aberrant phosphorylation of tau. Our findings suggest that cholesterol dyshomeostasis is an early event in the etiology of neurodegeneration caused by tau mutations. Competing Interests: Conflicts of interest The authors declare no competing interests. (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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