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The first knock-in rat model for glutaric aciduria type I allows further insights into pathophysiology in brain and periphery
- Source :
- Gonzalez Melo, Mary; Remacle, Noémie; Cudré-Cung, Hong-Phuc; Roux, Clothilde; Poms, Martin; Cudalbu, Cristina; Barroso, Madalena; Gersting, Søren Waldemar; Feichtinger, René Günther; Mayr, Johannes Adalbert; Costanzo, Michele; Caterino, Marianna; Ruoppolo, Margherita; Rüfenacht, Véronique; Häberle, Johannes; Braissant, Olivier; Ballhausen, Diana (2021). The first knock-in rat model for glutaric aciduria type I allows further insights into pathophysiology in brain and periphery. Molecular Genetics and Metabolism, 133(2):157-181.
- Publication Year :
- 2021
-
Abstract
- Glutaric aciduria type I (GA-I, OMIM # 231670) is an inborn error of metabolism caused by a deficiency of glutaryl-CoA dehydrogenase (GCDH). Patients develop acute encephalopathic crises (AEC) with striatal injury most often triggered by catabolic stress. The pathophysiology of GA-I, particularly in brain, is still not fully understood. We generated the first knock-in rat model for GA-I by introduction of the mutation p.R411W, the rat sequence homologue of the most common Caucasian mutation p.R402W, into the Gcdh gene of Sprague Dawley rats by CRISPR/CAS9 technology. Homozygous Gcdhki/ki rats revealed a high excretor phenotype, but did not present any signs of AEC under normal diet (ND). Exposure to a high lysine diet (HLD, 4.7%) after weaning resulted in clinical and biochemical signs of AEC. A significant increase of plasmatic ammonium concentrations was found in Gcdhki/ki rats under HLD, accompanied by a decrease of urea concentrations and a concomitant increase of arginine excretion. This might indicate an inhibition of the urea cycle. Gcdhki/ki rats exposed to HLD showed highly diminished food intake resulting in severely decreased weight gain and moderate reduction of body mass index (BMI). This constellation suggests a loss of appetite. Under HLD, pipecolic acid increased significantly in cerebral and extra-cerebral liquids and tissues of Gcdhki/ki rats, but not in WT rats. It seems that Gcdhki/ki rats under HLD activate the pipecolate pathway for lysine degradation. Gcdhki/ki rat brains revealed depletion of free carnitine, microglial activation, astroglyosis, astrocytic death by apoptosis, increased vacuole numbers, impaired OXPHOS activities and neuronal damage. Under HLD, Gcdhki/ki rats showed imbalance of intra- and extracellular creatine concentrations and indirect signs of an intracerebral ammonium accumulation. We successfully created the first rat model for GA-I. Characterization of this Gcdhki/ki strain confirmed that it is a suitable model not only
Details
- Database :
- OAIster
- Journal :
- Gonzalez Melo, Mary; Remacle, Noémie; Cudré-Cung, Hong-Phuc; Roux, Clothilde; Poms, Martin; Cudalbu, Cristina; Barroso, Madalena; Gersting, Søren Waldemar; Feichtinger, René Günther; Mayr, Johannes Adalbert; Costanzo, Michele; Caterino, Marianna; Ruoppolo, Margherita; Rüfenacht, Véronique; Häberle, Johannes; Braissant, Olivier; Ballhausen, Diana (2021). The first knock-in rat model for glutaric aciduria type I allows further insights into pathophysiology in brain and periphery. Molecular Genetics and Metabolism, 133(2):157-181.
- Notes :
- application/pdf, info:doi/10.5167/uzh-209459, English
- Publication Type :
- Electronic Resource
- Accession number :
- edsoai.on1443040935
- Document Type :
- Electronic Resource