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 journalArticlepeer-review

4 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 languageEnglish
Pages (from-to)98-109.e11
JournalCell Stem Cell
Volume27
Issue number1
DOIs
Publication statusPublished - 2 Jul 2020
Externally publishedYes

Keywords

  • cognition
  • disease modeling
  • genome editing
  • hippocampus
  • intellectual disability
  • learning
  • lipid metabolism
  • neural stem cell
  • neurogenesis
  • organoid

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