Department of Obstetrics, Gynecology & Reproductive Sciences, Baltimore, MD, USA.
Department of Obstetrics, Gynecology & Reproductive Sciences, Baltimore, MD, USA; Department of Biochemistry & Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Reprod Toxicol. 2019 Apr;85:51-58. doi: 10.1016/j.reprotox.2019.02.005. Epub 2019 Feb 12.
Autophagy is required for neurulation, and autophagy activators with minimal toxicity, such as the natural compound trehalose, a nonreducing disaccharide, possess high therapeutic value. To determine whether trehalose directly induces autophagy, FITC-labeled trehalose was used for tracing its presence in autophagosome complexes. Trehalose was as potent as rapamycin and starvation in inducing de novo autophagosome formation and increasing autophagosome flux in GFP-LC3 reporter cells and C17.2 neural stem cells. Trehalose effectively reversed high glucose-suppressed autophagy and reduced p62 protein expression. Trehalose abolished the disruption of autophagosome complexes under high glucose conditions in vitro and maternal diabetes in vivo. Autophagosomes induced by trehalose were functionally active, forming mitophagy and reticulophagy in removing damaged cellular organelles in neuroepithelial cells exposed to maternal diabetes. Thus, trehalose directly participated in functional autophagosome generation by incorporating itself into autophagosomes. These findings provide the mechanistic basis for the use of trehalose in preventing disruptive autophagy-associated pathogenesis.
自噬对于神经胚形成是必需的，并且具有最小毒性的自噬激活剂，如天然化合物海藻糖，是一种非还原性二糖，具有很高的治疗价值。为了确定海藻糖是否直接诱导自噬，使用 FITC 标记的海藻糖来追踪其在自噬体复合物中的存在。海藻糖与雷帕霉素和饥饿一样能够有效地诱导新的自噬体形成，并增加 GFP-LC3 报告细胞和 C17.2 神经干细胞中的自噬体流。海藻糖能有效逆转高葡萄糖抑制的自噬作用，减少 p62 蛋白的表达。海藻糖能消除高糖条件下体外和母体糖尿病体内自噬体复合物的破坏。海藻糖诱导的自噬体是功能活跃的，能形成线粒体自噬和网质体自噬，从而清除暴露于母体糖尿病的神经上皮细胞中受损的细胞细胞器。因此，海藻糖通过自身掺入自噬体来直接参与功能性自噬体的产生。这些发现为海藻糖在预防破坏性自噬相关发病机制中的应用提供了机制基础。
