|ZFIN ID: ZDB-PUB-181103-2|
Glycine decarboxylase deficiency-induced motor dysfunction in zebrafish is rescued by counterbalancing glycine synaptic level
Riché, R., Liao, M., Pena, I.A., Leung, K.Y., Lepage, N., Greene, N., Sarafoglou, K., Schimmenti, L.A., Drapeau, P., Samarut, É.
|Source:||JCI insight 3(21): (Journal)|
|Registered Authors:||Drapeau, Pierre, Samarut, Eric, Schimmenti, Lisa A.|
|Keywords:||Amino acid metabolism, Genetics, Neurological disorders, Neuroscience|
|PubMed:||30385710 Full text @ JCI Insight|
Riché, R., Liao, M., Pena, I.A., Leung, K.Y., Lepage, N., Greene, N., Sarafoglou, K., Schimmenti, L.A., Drapeau, P., Samarut, É. (2018) Glycine decarboxylase deficiency-induced motor dysfunction in zebrafish is rescued by counterbalancing glycine synaptic level. JCI insight. 3(21):.
ABSTRACTGlycine encephalopathy (GE), or nonketotic hyperglycinemia (NKH), is a rare recessive genetic disease caused by defective glycine cleavage and characterized by increased accumulation of glycine in all tissues. Here, based on new case reports of GLDC loss-of-function mutations in GE patients, we aimed to generate a zebrafish model of severe GE in order to unravel the molecular mechanism of the disease. Using CRISPR/Cas9, we knocked out the gldc gene and showed that gldc-/- fish recapitulate GE on a molecular level and present a motor phenotype reminiscent of severe GE symptoms. The molecular characterization of gldc-/- mutants showed a broad metabolic disturbance affecting amino acids and neurotransmitters other than glycine, with lactic acidosis at stages preceding death. Although a transient imbalance was found in cell proliferation in the brain of gldc-/- zebrafish, the main brain networks were not affected, thus suggesting that GE pathogenicity is mainly due to metabolic defects. We confirmed that the gldc-/- hypotonic phenotype is due to NMDA and glycine receptor overactivation, and demonstrated that gldc-/- larvae depict exacerbated hyperglycinemia at these synapses. Remarkably, we were able to rescue the motor dysfunction of gldc-/- larvae by counterbalancing pharmacologically or genetically the level of glycine at the synapse.