RRC ID 65895
Author Riché R, Liao M, Pena IA, Leung KY, Lepage N, Greene NDE, Sarafoglou K, Schimmenti LA, Drapeau P, Samarut É.
Title Glycine decarboxylase deficiency-induced motor dysfunction in zebrafish is rescued by counterbalancing glycine synaptic level.
Journal JCI Insight
Abstract Glycine 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.
Volume 3(21)
Published 2018-11-2
DOI 10.1172/jci.insight.124642
PII 124642
PMID 30385710
PMC PMC6238748
MeSH Animals Brain / diagnostic imaging Brain / metabolism Brain / physiopathology CRISPR-Associated Protein 9 / metabolism Dextromethorphan / administration & dosage Dextromethorphan / therapeutic use Excitatory Amino Acid Antagonists / therapeutic use Fatal Outcome Female Food Preservatives / therapeutic use Glycine / blood* Glycine / cerebrospinal fluid Glycine Dehydrogenase (Decarboxylating) / deficiency* Glycine Dehydrogenase (Decarboxylating) / metabolism Humans Hyperglycinemia, Nonketotic / diagnosis Hyperglycinemia, Nonketotic / enzymology Hyperglycinemia, Nonketotic / genetics* Infant, Newborn Male Middle Aged Motor Disorders / enzymology* Motor Disorders / physiopathology Mutation Phenotype Sodium Benzoate / administration & dosage Sodium Benzoate / therapeutic use Synaptic Transmission / drug effects* Treatment Outcome Zebrafish
IF 6.205
Zebrafish Tg(isl1:GFP) rw0 Tg(vglut2a:loxP-DsRed-loxP-GFP)