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  • 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
Paraformaldehyde, prilled, 95%
Sigma-Aldrich
Insulin solution human, sterile-filtered, BioXtra, suitable for cell culture
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5-Bromo-2′-deoxyuridine, BioUltra, ≥99%
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Tunicamycin from Streptomyces sp.
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Sodium phenylbutyrate, ≥98% (HPLC)
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Dorsomorphin, ≥98% (HPLC)
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Cerulenin, ≥98% (HPLC), from Cephalosporium caerulens
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Malonyl coenzyme A lithium salt, ≥90% (HPLC)
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Acetyl coenzyme A trisodium salt, ≥93% (HPLC), powder
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Poly-L-ornithine hydrobromide, mol wt 30,000-70,000
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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
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Heparin sodium salt from porcine intestinal mucosa, Grade I-A, ≥180 USP units/mg, powder, BioReagent, suitable for cell culture