FASN-Dependent Lipid Metabolism Links Neurogenic Stem/Progenitor Cell Activity to Learning and Memory Deficits
| Autor: | Thomas Wegleiter, Hossein Najmabadi, Rupert W. Overall, Megan Bowers, Werner J. Kovacs, Gerd Kempermann, Jochen Winterer, Baptiste N. Jaeger, Tong Liang, Clay F. Semenkovich, Sebastian Jessberger, Sara Zocher, Kaitlyn M.L. Cramb, Clemens Röhrl, Daniel Gonzalez-Bohorquez, Slavica Dimitrieva, Csaba Földy, Merit Kruse |
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| Přispěvatelé: | University of Zurich, Jessberger, Sebastian |
| Jazyk: | angličtina |
| Předmět: |
Neurogenesis
Regulator 610 Medicine & health Hippocampus 1307 Cell Biology Mice 03 medical and health sciences 0302 clinical medicine Neural Stem Cells 1311 Genetics ddc:570 Genetics Animals Progenitor cell Cell Proliferation 030304 developmental biology Memory Disorders 0303 health sciences 10242 Brain Research Institute biology Lipid metabolism Cell Biology Lipid Metabolism Embryonic stem cell Neural stem cell Cell biology Fatty acid synthase 1313 Molecular Medicine Forebrain biology.protein 570 Life sciences Molecular Medicine Fatty Acid Synthases 030217 neurology & neurosurgery |
| Zdroj: | Cell stem cell 27(1), 98-109.e11 (2020). doi:10.1016/j.stem.2020.04.002 |
| ISSN: | 1934-5909 |
| DOI: | 10.1016/j.stem.2020.04.002 |
| Popis: | Summary 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. |
| Databáze: | OpenAIRE |
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