FASN-Dependent Lipid Metabolism Links Neurogenic Stem/Progenitor Cell Activity to Learning and Memory Deficits.

Animals Cell Proliferation Fatty Acid Synthases Hippocampus Lipid Metabolism Memory Disorders Mice Neural Stem Cells Neurogenesis
cognition disease modeling genome editing hippocampus intellectual disability learning lipid metabolism neural stem cell neurogenesis organoid

Journal

Cell stem cell
ISSN: 1875-9777
Titre abrégé: Cell Stem Cell
Pays: United States
ID NLM: 101311472

Informations de publication

Date de publication:
02 07 2020
Historique:
received: 29 12 2019
revised: 19 02 2020
accepted: 09 04 2020
pubmed: 11 5 2020
medline: 28 4 2021
entrez: 11 5 2020
Statut: ppublish

Résumé

Altered neural stem/progenitor cell (NSPC) activity and neurodevelopmental defects are linked to intellectual disability. However, it remains unclear whether altered metabolism, a key regulator of NSPC activity, disrupts human neurogenesis and potentially contributes to cognitive defects. We investigated links between lipid metabolism and cognitive function in mice and human embryonic stem cells (hESCs) expressing mutant fatty acid synthase (FASN; R1819W), a metabolic regulator of rodent NSPC activity recently identified in humans with intellectual disability. Mice homozygous for the FASN R1812W variant have impaired adult hippocampal NSPC activity and cognitive defects because of lipid accumulation in NSPCs and subsequent lipogenic ER stress. Homozygous FASN R1819W hESC-derived NSPCs show reduced rates of proliferation in embryonic 2D cultures and 3D forebrain regionalized organoids, consistent with a developmental phenotype. These data from adult mouse models and in vitro models of human brain development suggest that altered lipid metabolism contributes to intellectual disability.

Identifiants

DOI: 10.1016/j.stem.2020.04.002 PMID: 32386572
pubmed: 32386572
pii: S1934-5909(20)30141-7
doi: 10.1016/j.stem.2020.04.002
pii:
doi:

Substances chimiques

Fatty Acid Synthases EC 2.3.1.85

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

98-109.e11

Informations de copyright

Copyright © 2020 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Interests The authors declare no competing interests.

Auteurs

Megan Bowers (M)

Laboratory of Neural Plasticity, Faculties of Medicine and Science, Brain Research Institute, University of Zurich, Zurich 8057, Switzerland.

Tong Liang (T)

Laboratory of Neural Plasticity, Faculties of Medicine and Science, Brain Research Institute, University of Zurich, Zurich 8057, Switzerland.

Daniel Gonzalez-Bohorquez (D)

Laboratory of Neural Plasticity, Faculties of Medicine and Science, Brain Research Institute, University of Zurich, Zurich 8057, Switzerland.

Sara Zocher (S)

German Center for Neurodegenerative Diseases (DZNE) Dresden and Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden 01307, Germany.

Baptiste N Jaeger (BN)

Laboratory of Neural Plasticity, Faculties of Medicine and Science, Brain Research Institute, University of Zurich, Zurich 8057, Switzerland.

Werner J Kovacs (WJ)

Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology (ETH) Zurich, Zurich 8093, Switzerland.

Clemens Röhrl (C)

Department of Medical Chemistry, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Vienna 1090, Austria.

Kaitlyn M L Cramb (KML)

Laboratory of Neural Plasticity, Faculties of Medicine and Science, Brain Research Institute, University of Zurich, Zurich 8057, Switzerland.

Jochen Winterer (J)

Laboratory of Neural Connectivity, Faculties of Medicine and Science, Brain Research Institute, University of Zurich, Zurich 8057, Switzerland.

Merit Kruse (M)

Laboratory of Neural Plasticity, Faculties of Medicine and Science, Brain Research Institute, University of Zurich, Zurich 8057, Switzerland.

Slavica Dimitrieva (S)

Functional Genomics Center Zurich, University and ETH Zurich, Zurich 8057, Switzerland.

Rupert W Overall (RW)

German Center for Neurodegenerative Diseases (DZNE) Dresden and Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden 01307, Germany.

Thomas Wegleiter (T)

Laboratory of Neural Plasticity, Faculties of Medicine and Science, Brain Research Institute, University of Zurich, Zurich 8057, Switzerland.

Hossein Najmabadi (H)

Genetics Research Center, University of Social Welfare and Rehabilitation, Teheran 1985713834, Iran.

Clay F Semenkovich (CF)

Washington University School of Medicine, Division of Endocrinology, Metabolism & Lipid Research, St. Louis, MO 63110, USA.

Gerd Kempermann (G)

German Center for Neurodegenerative Diseases (DZNE) Dresden and Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden 01307, Germany.

Csaba Földy (C)

Laboratory of Neural Connectivity, Faculties of Medicine and Science, Brain Research Institute, University of Zurich, Zurich 8057, Switzerland.

Sebastian Jessberger (S)

Laboratory of Neural Plasticity, Faculties of Medicine and Science, Brain Research Institute, University of Zurich, Zurich 8057, Switzerland. Electronic address: jessberger@hifo.uzh.ch.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › FASN-Dependent Lipid Metabolism Links...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Croissance › Processus de croissance cellulaire › Prolifération cellulaire › FASN-Dependent Lipid Metabolism Links...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › Acyltransferases › Acyl-carrier protein S-malonyltransferase › Fatty acid synthases › FASN-Dependent Lipid Metabolism Links...
questionsmedicales.fr › Système nerveux › Système nerveux central › Encéphale › Prosencéphale › Télencéphale › Cerveau › Cortex cérébral › Hippocampe › FASN-Dependent Lipid Metabolism Links...
questionsmedicales.fr › Métabolisme › Métabolisme lipidique › FASN-Dependent Lipid Metabolism Links...
questionsmedicales.fr › Comportement et mécanismes comportementaux › Manifestations neurocomportementales › Troubles de la mémoire › FASN-Dependent Lipid Metabolism Links...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › FASN-Dependent Lipid Metabolism Links...
questionsmedicales.fr › Cellules › Cellules souches › Cellules souches neurales › FASN-Dependent Lipid Metabolism Links...
questionsmedicales.fr › Phénomènes physiologiques de l'appareil locomoteur et du système nerveux › Phénomènes physiologiques du système nerveux › Neurogenèse › FASN-Dependent Lipid Metabolism Links...