PDF(Pubmed)
Abstract：
The pathophysiology of nonketotic hyperglycinemia (NKH), a rare neuro-metabolic disorder associated with severe brain malformations and life-threatening neurological manifestations, remains incompletely understood. Therefore, a valid human neural model is essential. We aimed to investigate the impact of GLDC gene variants, which cause NKH, on cellular fitness during the differentiation process of human induced pluripotent stem cells (iPSCs) into iPSC-derived astrocytes and to identify sustainable mechanisms capable of overcoming GLDC deficiency. We developed the GLDC27-FiPS4F-1 line and performed metabolomic, mRNA abundance, and protein analyses. This study showed that although GLDC27-FiPS4F-1 maintained the parental genetic profile, it underwent a metabolic switch to an altered serine-glycine-one-carbon metabolism with a coordinated cell growth and cell cycle proliferation response. We then differentiated the iPSCs into neural progenitor cells (NPCs) and astrocyte-lineage cells. Our analysis showed that GLDC-deficient NPCs had shifted towards a more heterogeneous astrocyte lineage with increased expression of the radial glial markers GFAP and GLAST and the neuronal markers MAP2 and NeuN. In addition, we detected changes in other genes related to serine and glycine metabolism and transport, all consistent with the need to maintain glycine at physiological levels. These findings improve our understanding of the pathology of nonketotic hyperglycinemia and offer new perspectives for therapeutic options.
摘要：
非酮症性高血糖症（NKH）的病理生理学，一种罕见的神经代谢紊乱，与严重的脑畸形和危及生命的神经表现有关，仍然不完全理解。因此,一个有效的人类神经模型是必不可少的。我们的目的是调查GLDC基因变异的影响，导致NKH，关于人诱导多能干细胞（iPSC）分化为iPSC衍生的星形胶质细胞过程中的细胞适应性，并确定能够克服GLDC缺乏的可持续机制。我们开发了GLDC27-FiPS4F-1系，并进行了代谢组学，mRNA丰度，和蛋白质分析。这项研究表明，尽管GLDC27-FiPS4F-1保持了亲本遗传特征，它经历了代谢转变为丝氨酸-甘氨酸-一碳代谢的改变,具有协调的细胞生长和细胞周期增殖反应.然后，我们将iPSC分化为神经祖细胞（NPC）和星形胶质细胞谱系细胞。我们的分析表明，缺乏GLDC的NPC已转向更加异质的星形胶质细胞谱系，放射状神经胶质标记物GFAP和GLAST以及神经元标记物MAP2和NeuN的表达增加。此外,我们检测到与丝氨酸和甘氨酸代谢和转运相关的其他基因的变化，都符合将甘氨酸维持在生理水平的需要。这些发现改善了我们对非酮症性高血糖的病理学的理解，并为治疗选择提供了新的视角。
