FASN-dependent metabolism links neurogenic stem/progenitor cell activity to intellectual disability

Failure of neural stem/progenitor cell (NSPC) activity and subsequently neurogenesis during brain development has been linked to cognitive impairment and intellectual disability. However, it remains unclear if changes in metabolism, recently discovered as a key regulator of somatic stem cell activity, contribute to altered neurogenesis and cognitive deficits in humans. To investigate a link between NSPC-associated lipid metabolism and brain development, we generated mice and human embryonic stem cells (hESCs) mimicking a variant in 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 hippocampal NSPC activity associated with cognitive impairment due to presumed toxic accumulation of lipids in NSPCs and subsequent lipogenic ER stress. Human NSPCs homozygous for the FASN R1819W variant show reduced rates of proliferation in embryonic 2D cultures and 3D forebrain regionalized organoids, revealing that the functional significance of lipid metabolism for neurogenic proliferation of progenitors is conserved between rodents and humans. By taking a disease modeling approach, using mouse and human tissue genome engineering, our data provide genetic evidence for a link between altered lipid metabolism, NSPC activity and brain function. Examination of i) 764 single-nuclei from NeuN+ hippocampal neurons isolated from 8.5-month-old WT (382 nuclei) and Fasn-R1812W mice (382 nuclei), ii) 764 single-nuclei from EdU+ hippocampal cells isolated from 8.5-month-old WT (382 nuclei) and Fasn-R1812W mice (382 nuclei), iii) 190 single-nuclei from embryonic cortices isolated from E14.5 WT (89 nuclei) and Fasn-R1812W mice (101 nuclei).