The first knock-in rat model for glutaric aciduria type I allows further insights into pathophysiology in brain and periphery
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The first knock-in rat model for glutaric aciduria type I allows further insights into pathophysiology in brain and periphery. / 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.
In: MOL GENET METAB, Vol. 133, No. 2, 06.2021, p. 157-181.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - The first knock-in rat model for glutaric aciduria type I allows further insights into pathophysiology in brain and periphery
AU - Gonzalez Melo, Mary
AU - Remacle, Noémie
AU - Cudré-Cung, Hong-Phuc
AU - Roux, Clothilde
AU - Poms, Martin
AU - Cudalbu, Cristina
AU - Barroso, Madalena
AU - Gersting, Søren Waldemar
AU - Feichtinger, René Günther
AU - Mayr, Johannes Adalbert
AU - Costanzo, Michele
AU - Caterino, Marianna
AU - Ruoppolo, Margherita
AU - Rüfenacht, Véronique
AU - Häberle, Johannes
AU - Braissant, Olivier
AU - Ballhausen, Diana
N1 - Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
PY - 2021/6
Y1 - 2021/6
N2 - 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 for the study of pathophysiological processes, but also for the development of new therapeutic interventions. We further brought up interesting new insights into the pathophysiology of GA-I in brain and periphery.
AB - 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 for the study of pathophysiological processes, but also for the development of new therapeutic interventions. We further brought up interesting new insights into the pathophysiology of GA-I in brain and periphery.
U2 - 10.1016/j.ymgme.2021.03.017
DO - 10.1016/j.ymgme.2021.03.017
M3 - SCORING: Journal article
C2 - 33965309
VL - 133
SP - 157
EP - 181
JO - MOL GENET METAB
JF - MOL GENET METAB
SN - 1096-7192
IS - 2
ER -
