Trehalose prevents neural tube defects by correcting maternal diabetes-suppressed autophagy and neurogenesis

Abstract

isting maternal diabetes increases the risk of neural tube defects (NTDs). The mechanism underlying maternal diabetes-induced NTDs is not totally defined, and its prevention remains a challenge. Autophagy, an intracellular process to degrade dysfunction protein and damaged cellular organelles, regulates cell proliferation, differentiation, and apoptosis. Because autophagy impairment causes NTDs reminiscent of those observed in diabetic pregnancies, we hypothesize that maternal diabetes-induced autophagy impairment causes NTD formation by disrupting cellular homeostasis, leading to endoplasmic reticulum (ER) stress and apoptosis, and that restoration of autophagy by trehalose, a natural disaccharide, prevents diabetes-induced NTDs. Embryos from nondiabetic and type 1 diabetic mice fed with or without 2 or 5% trehalose water were used to assess markers of autophagy, ER stress, and neurogenesis, numbers of autophagosomes, gene expression that regulates autophagy, NTD rates, indices of mitochondrial dysfunction, and neuroepithelial cell apoptosis. Maternal diabetes suppressed autophagy by significantly reducing LC3-II expression, autophagosome numbers, and GFP-LC3 punctate foci in neuroepithelial cells and by altering autophagy-related gene expression. Maternal diabetes delayed neurogenesis by blocking Sox1 neural progenitor differentiation. Trehalose treatment reversed autophagy impairment and prevented NTDs in diabetic pregnancies. Trehalose resolved homeostatic imbalance by correcting mitochondrial defects, dysfunctional proteins, ER stress, apoptosis, and delayed neurogenesis in the neural tubes exposed to hyperglycemia. Our study demonstrates for the first time that maternal diabetes suppresses autophagy in neuroepithelial cells of the developing neural tube, leading to NTD formation, and provides evidence for the potential efficacy of trehalose as an intervention against hyperglycemia-induced NTDs. diabetic embryopathy; autophagy; trehalose; neurogenesis; neural tube defects PREGESTATIONAL DIABETES significantly increases the risk of neural tube defects (NTDs), also known as diabetic embryopathy. There are three to 10 times more NTDs in the offspring of diabetic mothers than in those of nondiabetic mothers (3, 9, 36). Because optimal glycemic control is difficult to achieve and maintain, and even transient exposure to diabetes causes NTDs, maternal diabetes-induced NTDs are significant health problems for both the mother and child. The seriousness of these relationships is emphasized by the upsurge in diabetic pregnancies; nearly 3 million American women and 70 million women worldwide of reproductive age (18 -44 yr) have diabetes today, and this number is expected double by 2030. Although diabetic mellitus is a complex metabolic disease, hyperglycemia is the sole mediator of diabetes teratogenicity. Indeed, clinical studies have revealed a strong correlation between the degree of maternal hyperglycemia and the rate and severity of birth defects (15, 29). When whole rodent embryos are cultured in high concentra...

Curcumin ameliorates high glucose-induced neural tube defects by suppressing cellular stress and apoptosis

“…Oxidative stress caused by mutations in SOD1 and SOD2 promoter regions, that potentially affect the expression of these two antioxidant enzymes, may be responsible for the formation of human myelomeningocele, a type of NTDs 53 . Oxidative stress mediates the teratogenic effect of hyperglycemia by altering developmental gene expression that is essential for neural tube closure 7, 17 . Recent studies have revealed several important oxidative stress markers in maternal circulation for the early diagnosis of birth defects and other adverse fetal outcomes 51, 54, 55 .…”

Trehalose, an mTOR-Independent Inducer of Autophagy, Inhibits Human Cytomegalovirus Infection in Multiple Cell Types

“…We also wanted to induce autophagy in a way that would have the lowest probability of toxic effects. For that reason, we decided to use trehalose, a nontoxic disaccharide that has been shown to induce autophagy and to have neuroprotective effects in animal models of Huntington disease, Alzheimer's disease, Parkinson's disease, ALS, and maternal diabetes-associated neural tube defects in the embryo (13,(15)(16)(17)(18)(19)(20). In addition to the positive effects of trehalose in neurodegenerative diseases, there is also evidence that trehalose may have a beneficial effect on impaired endothelial cells in ageing arteries, a risk factor for cardiovascular disease (49).…”

“…It is known that neural tube defects are greatly increased in the offspring of women with pregestational diabetes. In a mouse model of maternal diabetes that leads to autophagy impairment in neuroepithelial cells and neural tube defects in the embryo, administration of trehalose in the drinking water prevents these neural tube defects (19,20). Although most studies have examined trehalose in the context of inducing macroautophagy, there is some evidence that it can also induce CMA and counter the effects of the proteasome inhibitor epoxomicin, including elevated reactive oxygen species (ROS), cleaved caspase 3, increased levels of ubiquitinated proteins, and mitochondrial dysfunction and altered morphology (21,22).…”

Advances in revealing the molecular targets downstream of oxidative stress–induced proapoptotic kinase signaling in diabetic embryopathy

“…We have previously demonstrated that apoptosis is implicated in diabetic embryopathy 2, 3, 5, 7, 16 . Our goal is to identify molecular intermediates of the apoptotic cascade responsible for diabetic embryopathy, with ultimately to provide a mechanistic basis for development of therapeutic agents.…”

“…We have used animal models to delineate the mechanism of maternal diabetes-induced malformations 1-5, 7, 8, 16 and specifically focused on the developing neural tube. We have previously demonstrated that apoptosis is implicated in diabetic embryopathy 2, 3, 5, 7, 16 .…”