論文 - 詳細
| RRC ID | 65895 |
|---|---|
| 著者 | Riché R, Liao M, Pena IA, Leung KY, Lepage N, Greene NDE, Sarafoglou K, Schimmenti LA, Drapeau P, Samarut É. |
| タイトル | Glycine decarboxylase deficiency-induced motor dysfunction in zebrafish is rescued by counterbalancing glycine synaptic level. |
| ジャーナル | 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. |
| 巻・号 | 3(21) |
| 公開日 | 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 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 7 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ゼブラフィッシュ | Tg(isl1:GFP) rw0 Tg(vglut2a:loxP-DsRed-loxP-GFP) |