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

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

Cell stem cell (2020-05-11)
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
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Cerulenin, ≥98% (HPLC), from Cephalosporium caerulens
Sigma-Aldrich
Malonyl coenzyme A lithium salt, ≥90% (HPLC)
Sigma-Aldrich
Heparin sodium salt from porcine intestinal mucosa, Grade I-A, ≥180 USP units/mg, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
Acetyl coenzyme A trisodium salt, ≥93% (HPLC), powder
Sigma-Aldrich
Laminin from Engelbreth-Holm-Swarm murine sarcoma basement membrane, 1-2 mg/mL in Tris-buffered saline, 0.2 μm filtered, BioReagent, suitable for cell culture
Sigma-Aldrich
Poly-L-ornithine hydrobromide, mol wt 30,000-70,000
Sigma-Aldrich
Dorsomorphin, ≥98% (HPLC)
Sigma-Aldrich
5-Bromo-2′-deoxyuridine, BioUltra, ≥99%
Sigma-Aldrich
Insulin solution human, sterile-filtered, BioXtra, suitable for cell culture
Sigma-Aldrich
Tunicamycin from Streptomyces sp.
Sigma-Aldrich
Paraformaldehyde, prilled, 95%
Sigma-Aldrich
EmbryoMax® Primary Mouse Embryonic Fibroblasts, PMEF, Strain CF1, Irradiated, Passage 3
Sigma-Aldrich
HumanKine® Thermostable bFGF,
Human Recombinant, Engineered bFGF growth factor with enchanced thermostability compared to the wild-type bFGF protein. Allows a less vigorous feeding schedule for human es/ips and neural stem cell culture.
Sigma-Aldrich
Sodium phenylbutyrate, ≥98% (HPLC)