FASN-Dependent Metabolism Links Neural Stem Cell Activity to Intellectual Disability

Failure of neural stem cell (NSC) 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 NSC-associated lipid metabolism and cognition we generated mice and human embryonic stem cells (hESCs) mimicking a variant in fatty acid synthase (FASN; R1819W), a metabolic regulator of rodent NSC activity recently identified in humans with intellectual disability. Strikingly, mice homozygous for the FASN R1812W variant have impaired hippocampal NSC activity associated with cognitive impairment due to presumed toxic accumulation of lipids in NSCs and subsequent lipogenic ER stress. Moreover, human NSCs (hNSCs) homozygous for the FASN R1819W variant show reduced rates of proliferation in 2D cultures and 3D forebrain regionalized organoids, revealing that the functional significance of lipid metabolism for NSC activity is conserved between rodents and humans. By taking a comprehensive disease modeling approach, using mouse and human tissue genome engineering, our data provide the first genetic evidence for a link between altered lipid metabolism, NSC activity and brain function in humans.