Human tau mutations in cerebral organoids induce a progressive dyshomeostasis of cholesterol.
MAPT mutation
astrocyte
brain organoid
cholesterol
disease model
neurodegeneration
single-cell RNA sequencing
tau
tauopathy
Journal
Stem cell reports
ISSN: 2213-6711
Titre abrégé: Stem Cell Reports
Pays: United States
ID NLM: 101611300
Informations de publication
Date de publication:
13 09 2022
13 09 2022
Historique:
received:
15
06
2022
revised:
18
07
2022
accepted:
19
07
2022
pubmed:
20
8
2022
medline:
17
9
2022
entrez:
19
8
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35985329
pii: S2213-6711(22)00371-X
doi: 10.1016/j.stemcr.2022.07.011
pmc: PMC9481908
pii:
doi:
Substances chimiques
tau Proteins
0
Cholesterol
97C5T2UQ7J
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2127-2140Subventions
Organisme : NIA NIH HHS
ID : P30 AG066444
Pays : United States
Organisme : NINDS NIH HHS
ID : U54 NS100717
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG026276
Pays : United States
Organisme : NINDS NIH HHS
ID : R35 NS097277
Pays : United States
Organisme : NIA NIH HHS
ID : R00 AG064116
Pays : United States
Organisme : NIH HHS
ID : S10 OD010786
Pays : United States
Organisme : NIA NIH HHS
ID : K99 AG064116
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG003991
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG056293
Pays : United States
Informations de copyright
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Conflicts of interest The authors declare no competing interests.
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