TY - JOUR
T1 - Glycine decarboxylase deficiency-induced motor dysfunction in zebrafish is rescued by counterbalancing glycine synaptic level
AU - Riché, Raphaëlle
AU - Liao, Meijiang
AU - Pena, Izabella A.
AU - Leung, Kit Yi
AU - Lepage, Nathalie
AU - Greene, Nicolas D.E.
AU - Sarafoglou, Kyriakie
AU - Schimmenti, Lisa A.
AU - Drapeau, Pierre
AU - Samarut, Éric
PY - 2018/11/2
Y1 - 2018/11/2
N2 - 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.
AB - 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.
KW - Amino acid metabolism
KW - Genetics
KW - Neurological disorders
KW - Neuroscience
KW - Inborn errors of metabolism
UR - http://www.scopus.com/inward/record.url?scp=85063240920&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85063240920&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.124642
DO - 10.1172/jci.insight.124642
M3 - Article
C2 - 30385710
AN - SCOPUS:85063240920
SN - 2379-3708
VL - 3
JO - JCI Insight
JF - JCI Insight
IS - 21
ER -