Arribas-Carreira, L.; Castro, M.; García, F.; Navarrete, R.; Bravo-Alonso, I.; Zafra, F.; Ugarte, M.; Richard, E.; Pérez, B.; Rodríguez-Pombo, P. Metabolic Rewiring and Altered Glial Differentiation in an iPSC-Derived Astrocyte Model Derived from a Nonketotic Hyperglycinemia Patient. Int. J. Mol. Sci.2024, 25, 2814.
Arribas-Carreira, L.; Castro, M.; García, F.; Navarrete, R.; Bravo-Alonso, I.; Zafra, F.; Ugarte, M.; Richard, E.; Pérez, B.; Rodríguez-Pombo, P. Metabolic Rewiring and Altered Glial Differentiation in an iPSC-Derived Astrocyte Model Derived from a Nonketotic Hyperglycinemia Patient. Int. J. Mol. Sci. 2024, 25, 2814.
Arribas-Carreira, L.; Castro, M.; García, F.; Navarrete, R.; Bravo-Alonso, I.; Zafra, F.; Ugarte, M.; Richard, E.; Pérez, B.; Rodríguez-Pombo, P. Metabolic Rewiring and Altered Glial Differentiation in an iPSC-Derived Astrocyte Model Derived from a Nonketotic Hyperglycinemia Patient. Int. J. Mol. Sci.2024, 25, 2814.
Arribas-Carreira, L.; Castro, M.; García, F.; Navarrete, R.; Bravo-Alonso, I.; Zafra, F.; Ugarte, M.; Richard, E.; Pérez, B.; Rodríguez-Pombo, P. Metabolic Rewiring and Altered Glial Differentiation in an iPSC-Derived Astrocyte Model Derived from a Nonketotic Hyperglycinemia Patient. Int. J. Mol. Sci. 2024, 25, 2814.
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 neuronal 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. The 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. 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 and offer new perspectives for therapeutic options.
Keywords
Human disease model; Inherited Metabolic Disorders; Inborn Error of Metabolism; Nonketotic Hyperglycinemia; GLDC; iPSC; iPSC-derived astrocytes; serine-glycine-one-carbon metabolism
Subject
Biology and Life Sciences, Biochemistry and Molecular Biology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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