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

Megan Bowers; Tong Liang; Daniel Gonzalez-Bohorquez; Sara Zocher; Baptiste N. Jaeger; Werner J. Kovacs; Clemens Röhrl; Kaitlyn M.L. Cramb; Jochen Winterer; Merit Kruse; Slavica Dimitrieva; Rupert W. Overall; Thomas Wegleiter; Hossein Najmabadi; Clay F. Semenkovich; Gerd Kempermann; Csaba Földy; Sebastian Jessberger

doi:10.1016/j.stem.2020.04.002

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

Megan Bowers, Tong Liang, Daniel Gonzalez-Bohorquez, Sara Zocher, Baptiste N. Jaeger, Werner J. Kovacs, Clemens Röhrl, Kaitlyn M.L. Cramb, Jochen Winterer, Merit Kruse, Slavica Dimitrieva, Rupert W. Overall, Thomas Wegleiter, Hossein Najmabadi, Clay F. Semenkovich, Gerd Kempermann, Csaba Földy, Sebastian Jessberger

Research output: Contribution to journal › Article › peer-review

60 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	98-109.e11
Journal	Cell Stem Cell
Volume	27
Issue number	1
DOIs	https://doi.org/10.1016/j.stem.2020.04.002
Publication status	Published - 2 Jul 2020
Externally published	Yes

Keywords

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

Access to Document

10.1016/j.stem.2020.04.002

Cite this

Bowers, M., Liang, T., Gonzalez-Bohorquez, D., Zocher, S., Jaeger, B. N., Kovacs, W. J., Röhrl, C., Cramb, K. M. L., Winterer, J., Kruse, M., Dimitrieva, S., Overall, R. W., Wegleiter, T., Najmabadi, H., Semenkovich, C. F., Kempermann, G., Földy, C., & Jessberger, S. (2020). FASN-Dependent Lipid Metabolism Links Neurogenic Stem/Progenitor Cell Activity to Learning and Memory Deficits. Cell Stem Cell, 27(1), 98-109.e11. https://doi.org/10.1016/j.stem.2020.04.002

@article{1c837e8d27234ee6bdda0d6a4869e769,

title = "FASN-Dependent Lipid Metabolism Links Neurogenic Stem/Progenitor Cell Activity to Learning and Memory Deficits",

abstract = "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.",

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

author = "Megan Bowers and Tong Liang and Daniel Gonzalez-Bohorquez and Sara Zocher and Jaeger, {Baptiste N.} and Kovacs, {Werner J.} and Clemens R{\"o}hrl and Cramb, {Kaitlyn M.L.} and Jochen Winterer and Merit Kruse and Slavica Dimitrieva and Overall, {Rupert W.} and Thomas Wegleiter and Hossein Najmabadi and Semenkovich, {Clay F.} and Gerd Kempermann and Csaba F{\"o}ldy and Sebastian Jessberger",

note = "Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = jul,

day = "2",

doi = "10.1016/j.stem.2020.04.002",

language = "English",

volume = "27",

pages = "98--109.e11",

journal = "Cell Stem Cell",

issn = "1934-5909",

publisher = "Cell Press",

number = "1",

}

Bowers, M, Liang, T, Gonzalez-Bohorquez, D, Zocher, S, Jaeger, BN, Kovacs, WJ, Röhrl, C, Cramb, KML, Winterer, J, Kruse, M, Dimitrieva, S, Overall, RW, Wegleiter, T, Najmabadi, H, Semenkovich, CF, Kempermann, G, Földy, C & Jessberger, S 2020, 'FASN-Dependent Lipid Metabolism Links Neurogenic Stem/Progenitor Cell Activity to Learning and Memory Deficits', Cell Stem Cell, vol. 27, no. 1, pp. 98-109.e11. https://doi.org/10.1016/j.stem.2020.04.002

TY - JOUR

T1 - FASN-Dependent Lipid Metabolism Links Neurogenic Stem/Progenitor Cell Activity to Learning and Memory Deficits

AU - Bowers, Megan

AU - Liang, Tong

AU - Gonzalez-Bohorquez, Daniel

AU - Zocher, Sara

AU - Jaeger, Baptiste N.

AU - Kovacs, Werner J.

AU - Röhrl, Clemens

AU - Cramb, Kaitlyn M.L.

AU - Winterer, Jochen

AU - Kruse, Merit

AU - Dimitrieva, Slavica

AU - Overall, Rupert W.

AU - Wegleiter, Thomas

AU - Najmabadi, Hossein

AU - Semenkovich, Clay F.

AU - Kempermann, Gerd

AU - Földy, Csaba

AU - Jessberger, Sebastian

PY - 2020/7/2

Y1 - 2020/7/2

N2 - 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.

AB - 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.

KW - cognition

KW - disease modeling

KW - genome editing

KW - hippocampus

KW - intellectual disability

KW - learning

KW - lipid metabolism

KW - neural stem cell

KW - neurogenesis

KW - organoid

KW - Cell Proliferation

KW - Lipid Metabolism

KW - Neural Stem Cells

KW - Neurogenesis

KW - Memory Disorders

KW - Animals

KW - Fatty Acid Synthases

KW - Mice

KW - Hippocampus

UR - http://www.scopus.com/inward/record.url?scp=85084825093&partnerID=8YFLogxK

U2 - 10.1016/j.stem.2020.04.002

DO - 10.1016/j.stem.2020.04.002

M3 - Article

C2 - 32386572

AN - SCOPUS:85084825093

SN - 1934-5909

VL - 27

SP - 98-109.e11

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 1

ER -

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

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this