FASN-Dependent Lipid Metabolism Links Neurogenic Stem/Progenitor Cell Activity to Learning and Memory Deficits

被引：76

作者：

Bowers, Megan ^{[1
,2
]}

Liang, Tong ^{[1
,2
]}

Gonzalez-Bohorquez, Daniel ^{[1
,2
]}

Zocher, Sara ^{[3
,4
]}

Jaeger, Baptiste N. ^{[1
,2
]}

Kovacs, Werner J. ^{[5
]}

Roehrl, Clemens ^{[6
]}

Cramb, Kaitlyn M. L. ^{[1
,2
]}

Winterer, Jochen ^{[2
,7
]}

Kruse, Merit ^{[1
,2
]}

Dimitrieva, Slavica ^{[8
,9
]}

Overall, Rupert W. ^{[3
,4
]}

Wegleiter, Thomas ^{[1
,2
]}

Najmabadi, Hossein ^{[10
]}

Semenkovich, Clay F. ^{[11
]}

Kempermann, Gerd ^{[3
,4
]}

Foldy, Csaba ^{[2
,7
]}

Jessberger, Sebastian ^{[1
,2
]}

机构：

[1] Univ Zurich, Brain Res Inst, Fac Med, Lab Neural Plast, CH-8057 Zurich, Switzerland

[2] Univ Zurich, Brain Res Inst, Fac Sci, CH-8057 Zurich, Switzerland

[3] Tech Univ Dresden, German Ctr Neurodegenerat Dis DZNE Dresden, D-01307 Dresden, Germany

[4] Tech Univ Dresden, CRTD, D-01307 Dresden, Germany

[5] Swiss Fed Inst Technol, Dept Biol, Inst Mol Hlth Sci, CH-8093 Zurich, Switzerland

[6] Med Univ Vienna, Dept Med Chem, Ctr Pathobiochem & Genet, A-1090 Vienna, Austria

[7] Univ Zurich, Brain Res Inst, Fac Med, Lab Neural Connect, CH-8057 Zurich, Switzerland

[8] Univ Zurich, Funct Genom Ctr Zurich, CH-8057 Zurich, Switzerland

[9] Swiss Fed Inst Technol, CH-8057 Zurich, Switzerland

[10] Univ Social Welf & Rehabil, Genet Res Ctr, Tehran 1985713834, Iran

[11] Washington Univ, Sch Med, Div Endocrinol Metab & Lipid Res, St Louis, MO 63110 USA

来源：

CELL STEM CELL | 2020年 / 27卷 / 01期

基金：

欧洲研究理事会; 瑞士国家科学基金会;

关键词：

FATTY-ACID SYNTHASE; ENDOPLASMIC-RETICULUM STRESS; UNFOLDED PROTEIN RESPONSE; HIPPOCAMPAL NEUROGENESIS; RADIAL GLIA; ER STRESS; RNA-SEQ; BRAIN; OXIDATION; REGION;

D O I：

10.1016/j.stem.2020.04.002

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

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.

引用

页码：98 / +

页数：23

共 59 条

[1] 24(S)-hydroxycholesterol participates in a liver X receptor-controlled pathway in astrocytes that regulates apolipoprotein E-mediated cholesterol efflux [J].