Laboratory of Neural Plasticity, Faculties of Medicine and Science, Brain Research Institute, University of Zurich, 8057 Zurich, Switzerland.
Department of Neuroscience, University of Wisconsin-Madison, Madison, WI 53705, USA.
Cell Stem Cell. 2021 May 6;28(5):967-977.e8. doi: 10.1016/j.stem.2021.01.015. Epub 2021 Feb 24.
Neural stem cells (NSCs) generate neurons throughout life in the hippocampal dentate gyrus. With advancing age, levels of neurogenesis sharply drop, which has been associated with a decline in hippocampal memory function. However, cell-intrinsic mechanisms mediating age-related changes in NSC activity remain largely unknown. Here, we show that the nuclear lamina protein lamin B1 (LB1) is downregulated with age in mouse hippocampal NSCs, whereas protein levels of SUN-domain containing protein 1 (SUN1), previously implicated in Hutchinson-Gilford progeria syndrome (HGPS), increase. Balancing the levels of LB1 and SUN1 in aged NSCs restores the strength of the endoplasmic reticulum diffusion barrier that is associated with segregation of aging factors in proliferating NSCs. Virus-based restoration of LB1 expression in aged NSCs enhances stem cell activity in vitro and increases progenitor cell proliferation and neurogenesis in vivo. Thus, we here identify a mechanism that mediates age-related decline of neurogenesis in the mammalian hippocampus.
神经干细胞（NSCs）在海马齿状回中终生产生神经元。随着年龄的增长，神经发生的水平急剧下降，这与海马记忆功能的下降有关。然而，介导 NSC 活性与年龄相关变化的细胞内在机制在很大程度上仍是未知的。在这里，我们表明核纤层蛋白 LB1（LB1）在小鼠海马 NSCs 中随年龄下降，而先前与哈钦森-吉尔福德早衰综合征（HGPS）有关的 SUN 结构域蛋白 1（SUN1）的蛋白水平增加。在衰老的 NSCs 中平衡 LB1 和 SUN1 的水平可恢复内质网扩散屏障的强度，该屏障与增殖 NSCs 中衰老因子的隔离有关。基于病毒的 LB1 表达在衰老 NSCs 中的恢复增强了体外干细胞的活性，并增加了体内祖细胞的增殖和神经发生。因此，我们在这里确定了一种介导哺乳动物海马神经发生与年龄相关下降的机制。
