Cell Stem Cell . . . Liang Qi and so on reveal the lipid metabolism to regulate the activity of nerve stem progenitor cells and learn memory.

Neural stem / progenitor cell (NSPC) is not only responsible for the early development of the brain, but also affects the learning and memory functions of the brain by continuously dividing and producing new neurons in the adult stage.studies have found that many gene changes can damage the activity of NSPC and lead to a variety of nervous system diseases including cognitive impairment.in recent years, scientists have found that lipid metabolism plays an important role in regulating the activity of NSPC in adult mice and adult neurogenesis (AHN) in hippocampus.Sebastian, Institute of brain research, University of Zurich In 2013, jessberger's research group found that specific knockout of fatty acid synthase (FASN) in the dentate gyrus (DG) of adult mice could inhibit the division of NSPC and significantly reduce the level of Ahn [1]. However, little is known about the effects of lipid metabolism and its changes on human neurogenesis and brain cognitive function.on May 7, 2020, Sebastian jessberger team (as Megan Bowers, Liang Tong and Daniel Gonzalez bohorquez) published in cell stem cell magazine the FASN dependent lipid metabolism links neurogenic stem / producer cell activity to learning and memory In the long article of deficits, we systematically reported the regulation of lipid metabolism mediated by fatty acid synthase on NSPC activity and their relationship with learning and memory deficits.although there is still a lack of knowledge about the regulation of lipid metabolism on human NSPC (hnspc) activity and adult neurogenesis, in 2011, Najmabadi published a report on a mutant of fatty acid synthase (fasn-r1819w), and individuals with homozygotes of this mutant will show significant intellectual disability in childhood [2].to study whether this mental disability is related to lipid metabolism disorder and NSPC activity changes caused by the mutant, jessberger team established a mouse model (fasn-r1812w) containing the mutant, and used crisp / cas9 gene editing technology to establish the hnspc and forebrain organs containing human mutant (fasn-r1819w).the researchers first studied the effects of the mutant on NSPC activity and Ahn in the dentate gyrus of adult mice.the results showed that NSPC isolated from the dentate gyrus of fasn-r1812w mice showed significantly decreased cell proliferation in vitro; meanwhile, in vivo results showed that the Ahn level of fasn-r1812w mice decreased significantly at 9 months old, but the structure and function of other brain regions were normal.therefore, the results suggest that fasn-r1812w has a tissue-specific effect on the brain.next, the molecular mechanism of r1812w mutant affecting NSPC was studied.they speculated that r1812w mutant may cause the inactivation of FASN in NSPC of dentate gyrus, resulting in decreased proliferation of NSPC.unexpectedly, the researchers found that the activity of FASN in the dentate gyrus containing the mutant did not decrease but increased, and the abnormally increased FASN activity caused the harmful accumulation of lipids in NSPC.QRT PCR analysis showed that the accumulation of lipids led to the increase of endoplasmic reticulum stress related genes in NSPC. Therefore, the researchers speculated that r1812w mutant could affect the proliferation of NSPC by stimulating lipogenic ER stress.to further verify this hypothesis, the researchers used endoplasmic reticulum stress inhibitors (4pba and TUDCA) to treat NSPC containing the mutant.the results showed that the proliferation of NSPC with mutant treated with 4pba and TUDCA could recover to the level of control group.these results suggest that fasn-r1812w mutation can cause abnormal lipid accumulation in NSPC, and thus activate lipogenic ER stress, which leads to the decline of NSPC proliferation. as the Ahn level of fasn-r1812w mice was significantly decreased, in order to study the effect of the mutant on the behavior of mice, the Morris water maze test was used to detect the type of reference memory. the results showed that fasn-r1812w mice showed neurogenesis dependent memory impairment in hippocampus. in order to further study the effect of the mutant on the function of hnspc, the researchers established human embryonic stem cell-derived hnsspcs containing the mutant through crisp / cas9 gene editing technology. the results showed that the mutant could reduce the proliferation level of hnspc in vitro, and increase the endoplasmic reticulum stress level. next, the researchers also established a forebrain like organ containing the mutant, and found that the mutation could lead to a decrease in the proliferation of cortical progenitor cells. in this study, we reported for the first time the functional relationship between lipid metabolism disorder and NSPC activity and brain cognitive function by studying the fatty acid synthase mutant (fasn-r1819w) found in patients with mental retardation. at the same time, they found that the mutation of fatty acid synthase, a key enzyme of de novo lipogenesis, impaired the proliferation of NSPC by inducing lipid accumulation and endoplasmic reticulum stress in mice and human NSPC, resulting in decreased Ahn level and neurogenesis dependent memory impairment in hippocampus. therefore, this study provides a potential therapeutic approach to improve human mental retardation by targeting lipid synthesis and / or endoplasmic reticulum stress in NSPC. 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