PUBLICATION
Glycine decarboxylase deficiency-induced motor dysfunction in zebrafish is rescued by counterbalancing glycine synaptic level
- Authors
- Riché, R., Liao, M., Pena, I.A., Leung, K.Y., Lepage, N., Greene, N., Sarafoglou, K., Schimmenti, L.A., Drapeau, P., Samarut, É.
- ID
- ZDB-PUB-181103-2
- Date
- 2018
- Source
- JCI insight 3(21): (Journal)
- Registered Authors
- Drapeau, Pierre, Samarut, Eric, Schimmenti, Lisa A.
- Keywords
- Amino acid metabolism, Genetics, Neurological disorders, Neuroscience
- MeSH Terms
-
- 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
- PubMed
- 30385710 Full text @ JCI Insight
Citation
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):.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping