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Tytuł:
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The first knock-in rat model for glutaric aciduria type I allows further insights into pathophysiology in brain and periphery.
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Autorzy:
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Gonzalez Melo M; Pediatric Metabolic Unit, Pediatrics, Woman-Mother-Child Department, University of Lausanne and University Hospital of Lausanne, Switzerland. Electronic address: .
Remacle N; Pediatric Metabolic Unit, Pediatrics, Woman-Mother-Child Department, University of Lausanne and University Hospital of Lausanne, Switzerland.
Cudré-Cung HP; Pediatric Metabolic Unit, Pediatrics, Woman-Mother-Child Department, University of Lausanne and University Hospital of Lausanne, Switzerland.
Roux C; Service of Clinical Chemistry, University of Lausanne and University Hospital of Lausanne, Switzerland. Electronic address: .
Poms M; Klinische Chemie und Biochemie Universitäts-Kinderspital Zürich, Switzerland. Electronic address: .
Cudalbu C; CIBM Center for Biomedical Imaging, Switzerland; Animal Imaging and Technology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. Electronic address: .
Barroso M; University Children's Research, , University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: .
Gersting SW; University Children's Research, , University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: .
Feichtinger RG; Department of Pediatrics, University Hospital Salzburg, Paracelsus Medical University, Salzburg, Austria. Electronic address: .
Mayr JA; Department of Pediatrics, University Hospital Salzburg, Paracelsus Medical University, Salzburg, Austria. Electronic address: .
Costanzo M; Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, Italy; CEINGE - Biotecnologie Avanzate s.c.ar.l., 80145 Naples, Italy. Electronic address: .
Caterino M; Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, Italy; CEINGE - Biotecnologie Avanzate s.c.ar.l., 80145 Naples, Italy. Electronic address: .
Ruoppolo M; Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, Italy; CEINGE - Biotecnologie Avanzate s.c.ar.l., 80145 Naples, Italy. Electronic address: .
Rüfenacht V; Division of Metabolism and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland. Electronic address: .
Häberle J; Division of Metabolism and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland. Electronic address: .
Braissant O; Service of Clinical Chemistry, University of Lausanne and University Hospital of Lausanne, Switzerland. Electronic address: .
Ballhausen D; Pediatric Metabolic Unit, Pediatrics, Woman-Mother-Child Department, University of Lausanne and University Hospital of Lausanne, Switzerland. Electronic address: .
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Źródło:
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Molecular genetics and metabolism [Mol Genet Metab] 2021 Jun; Vol. 133 (2), pp. 157-181. Date of Electronic Publication: 2021 Apr 18.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Original Publication: Orlando, FL : Academic Press, c1998-
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MeSH Terms:
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Amino Acid Metabolism, Inborn Errors/*genetics
Brain/*metabolism
Brain Diseases, Metabolic/*genetics
Gliosis/*genetics
Glutaryl-CoA Dehydrogenase/*deficiency
Glutaryl-CoA Dehydrogenase/*genetics
Amino Acid Metabolism, Inborn Errors/metabolism ; Amino Acid Metabolism, Inborn Errors/pathology ; Animals ; Arginine/metabolism ; Brain/pathology ; Brain Diseases, Metabolic/metabolism ; Brain Diseases, Metabolic/pathology ; Creatine/blood ; Disease Models, Animal ; Gene Knock-In Techniques ; Gliosis/metabolism ; Gliosis/pathology ; Glutaryl-CoA Dehydrogenase/metabolism ; Humans ; Lysine/metabolism ; Metabolism, Inborn Errors/genetics ; Metabolism, Inborn Errors/metabolism ; Rats
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Contributed Indexing:
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Keywords: Astrogliosis; Cerebral organic aciduria; Glutaric aciduria type I; Hyperammonemia; Lysine degradation; Microglial activation
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Substance Nomenclature:
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94ZLA3W45F (Arginine)
EC 1.3.8.6 (Glutaryl-CoA Dehydrogenase)
K3Z4F929H6 (Lysine)
MU72812GK0 (Creatine)
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SCR Disease Name:
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Glutaric Acidemia I
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Entry Date(s):
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Date Created: 20210509 Date Completed: 20210910 Latest Revision: 20210910
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Update Code:
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20240105
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DOI:
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10.1016/j.ymgme.2021.03.017
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PMID:
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33965309
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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 Gcdh ki/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 Gcdh ki/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. Gcdh ki/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 Gcdh ki/ki rats, but not in WT rats. It seems that Gcdh ki/ki rats under HLD activate the pipecolate pathway for lysine degradation. Gcdh ki/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, Gcdh ki/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 Gcdh ki/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.
(Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
