Zebrafish model of Glycine Encephalopathy
Glycine encephalopathy (GE) is a rare recessive genetic disease caused by defective glycine cleavage and characterized by increased accumulation of glycine in all tissues. In severe GE, patients have a high lethality in the first week of life, hypotonia, lethargy, and survive with variable developmental delay and intractable seizures. The treatments available are often inefficient on the severe form of the disease and little translational research has focused on the pathogenic mechanisms involved in GE. Here, we generated a zebrafish model of severe GE by knocking out the ortholog of the ‘GLycine DeCarboxylase’ gene GLDC, commonly mutated in the disease. We show that the gldc -/- zebrafish larvae recapitulate GE on a molecular level, with reduced gldc expression and increased glycine levels in the body. Gldc - /- also shows a phenotype reminiscent of severe GE symptoms, such as early lethality, hypotonia, and lethargy. A broad molecular characterization of gldc -/- mutants showed that there is a large metabolic disturbance affecting other amino acids and neurotransmitters than glycine, with lactic acidosis at stages preceding death. A transient imbalance was found in cell proliferation in the brain of gldc -/- but that does not have obvious consequences on major brain networks. Importantly, we confirmed that the gldc -/- hypotonic phenotype is due to NMDA and glycine receptor overactivation and demonstrated that there is an exacerbated hyperglycinemia at these synapses, which can be rescued pharmacologically using NMDA and/or glycine receptor antagonists, as well as genetically by overexpressing the glycine transporter GlyT1.
glycinergic encephalopathy glycine metabolism gldc zebrafish genetic translational