PDF(Pubmed)
Abstract：
Adult neural stem cells (NSCs) in the hippocampal dentate gyrus continuously proliferate and generate new neurons throughout life. Although various functions of organelles are closely related to the regulation of adult neurogenesis, the role of endoplasmic reticulum (ER)-related molecules in this process remains largely unexplored. Here we show that Derlin-1, an ER-associated degradation component, spatiotemporally maintains adult hippocampal neurogenesis through a mechanism distinct from its established role as an ER quality controller. Derlin-1 deficiency in the mouse central nervous system leads to the ectopic localization of newborn neurons and impairs NSC transition from active to quiescent states, resulting in early depletion of hippocampal NSCs. As a result, Derlin-1-deficient mice exhibit phenotypes of increased seizure susceptibility and cognitive dysfunction. Reduced Stat5b expression is responsible for adult neurogenesis defects in Derlin-1-deficient NSCs. Inhibition of histone deacetylase activity effectively induces Stat5b expression and restores abnormal adult neurogenesis, resulting in improved seizure susceptibility and cognitive dysfunction in Derlin-1-deficient mice. Our findings indicate that the Derlin-1-Stat5b axis is indispensable for the homeostasis of adult hippocampal neurogenesis.
摘要：
海马齿状回中的成体神经干细胞(NSCs)在整个生命中不断增殖并产生新的神经元。尽管细胞器的各种功能与成人神经发生的调节密切相关。内质网(ER)相关分子在这一过程中的作用在很大程度上仍未被研究.在这里，我们展示了Derlin-1，一种与ER相关的降解成分，通过与其作为ER质量控制器的既定作用不同的机制，时空维持成年海马神经发生。小鼠中枢神经系统中的Derlin-1缺乏导致新生神经元的异位定位，并损害NSC从活跃状态到静止状态的过渡，导致海马神经干细胞早期耗尽。因此,Derlin-1缺陷型小鼠表现出癫痫发作易感性和认知功能障碍增加的表型。Stat5b表达减少是Derlin-1缺陷型NSC中成人神经发生缺陷的原因。抑制组蛋白脱乙酰酶活性可有效诱导Stat5b表达并恢复异常的成人神经发生，导致Derlin-1缺陷小鼠癫痫发作易感性和认知功能障碍的改善。我们的发现表明，Derlin-1-Stat5b轴对于成年海马神经发生的稳态是必不可少的。
