Excessive apoptosis and ROS induced by ethionine affect neural cell viability and differentiation

Abstract

The central nervous system (CNS) diseases are still a major cause of morbidity and mortality throughout the world, which imposes heavy burden on the development of society. Ethionine is a non-proteinogenic amino acid having similar chemical structure and activity to that of methionine, with which it competes. Previous studies have confirmed that ethionine affects various cellular functions by inhibiting the biosynthesis of proteins, RNA, DNA, and phospholipids, or all of them. The relationship of ethionine with some CNS diseases, including neural tube defects, has been investigated recently. However, the detailed effects of ethionine on the nerve cell bioactivities and the underlying mechanisms have not been fully explored. Herein, we systematically investigated the influences of ethionine on the proliferation, differentiation, and apoptosis of neural stem cells (NSCs) and post-mitotic nerve cells. We demonstrated that ethionine inhibited cell viability by disrupting the balance between proliferation and apoptosis, prevented NSCs from differentiating into neurons and astrocytes, and blocked cell progression from G1 to S phase via reducing cyclin D1 function in nerve cells including NSCs, a mouse hippocampal neuron cell line (HT-22), and a mouse brain neuroma cell line (Neuro-2a). We speculated that the inhibitory effect of ethionine on cell viability and differentiation are associated with increased reactive oxygen species production. Our results also supported the concept that ethionine may be an underlying cause of abnormal folate metabolism-induced CNS diseases. Our findings may provide important direction for the application of abnormal folate metabolism-induced CNS diseases in future NSC-based therapies.

Ethionine-mediated reduction of S-adenosylmethionine is responsible for the neural tube defects in the developing mouse embryo-mediated m6A modification and is involved in neural tube defects via modulating Wnt/β-catenin signaling pathway

“…The cell cycle detection kit (KeyGEN, Suzhou, China) was used for the cell cycle analysis. Then the cell apoptosis and cell cycle assay were performed as described previously [ 10 ]. Experiments were performed three times for each group.…”

“…Ethionine is a natural compound, and it is an S -ethyl analog of methionine with a small change in structure [ 9 , 10 ]. It competes with methionine in combination with methyladenosyltransferase (MAT), leading to a reduction in S -adenosylmethionine (SAM) during the synthesis of DNAs, RNAs and proteins [ 11 ].…”

Reduced H3K27me3 Suppresses Wnt/β-catenin Signaling by S-adenosylmethionine Deficiency in Neural Tube Development

“…To further prove the role of SAM in histone methylation, we have determined the histone methylation levels in neural stem cells. The neural stem cells (NSCs) were obtained from E13.5 mouse embryos, which were major cell types in CNS development [17]. The morphology of NSCs isolated from the mouse embryos was normal and globular in appearance (Figs.…”

Reduced H3K27me3 suppresses Wnt/β-catenin signaling by S-adenosylmethionine deficiency in neural tube development

“…To further prove the role of SAM in histone methylation, we have determined the histone methylation levels in neural stem cells. The neural stem cells (NSCs) were obtained from E13.5 mouse embryos, which were major cell types in CNS development [17]. The morphology of NSCs isolated from the mouse embryos was normal and globular in appearance (Figures 3A-D).…”