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
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DOI：
10.1016/j.stem.2020.04.002
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发表时间：
2020-07-02
期刊：
影响因子：
23.9
通讯作者：
Jessberger, Sebastian
中科院分区：
文献类型：
--
作者：
Bowers, Megan;Liang, Tong;Jessberger, Sebastian
神经干细胞/祖细胞(NSPC)活性改变和神经发育缺陷与智力残疾有关。然而，作为NSPC活动的关键调节因素，新陈代谢的改变是否会扰乱人类的神经发生，并可能导致认知缺陷，目前尚不清楚。我们研究了小鼠和表达突变脂肪酸合成酶(FASN；R1819W)的人类胚胎干细胞(HESCs)之间的脂肪代谢和认知功能之间的联系，FASN；R1819W是最近在智力残疾的人类中发现的啮齿动物NSPC活动的代谢调节因子。FASN R1812W变异纯合子小鼠由于NSPC中的脂质积累和随后的造脂内质网应激，已经损害了成年海马NSPC的活动和认知缺陷。纯合子FASN R1819W hESC来源的NSPC在2D胚胎培养和3D前脑区域化器官样体中的增殖率降低，这与发育表型一致。这些来自成年小鼠模型和人类大脑发育体外模型的数据表明，脂肪代谢的改变有助于智力残疾。
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.