Melo, Mary GonzalezRemacle, NoemieCudre-Cung, Hong-PhucRoux, ClothildePoms, MartinCudalbu, CristinaBarroso, MadalenaGersting, Soren WaldemarFeichtinger, Rene GuntherMayr, Johannes AdalbertCostanzo, MicheleCaterino, MariannaRuoppolo, MargheritaRufenacht, VeroniqueHaberle, JohannesBraissant, OlivierBallhausen, Diana2021-07-032021-07-032021-07-032021-06-0110.1016/j.ymgme.2021.03.017https://infoscience.epfl.ch/handle/20.500.14299/179745WOS:000659056900004Glutaric 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 ther-apeutic interventions. We further brought up interesting new insights into the pathophysiology of GA-I in brain and periphery.(c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).Endocrinology & MetabolismGenetics & HeredityMedicine, Research & ExperimentalEndocrinology & MetabolismGenetics & HeredityResearch & Experimental Medicineglutaric aciduria type icerebral organic acidurialysine degradationhyperammonemiaastrogliosismicroglial activationmouse modellysine metabolismmicroglial activationenergy-metabolismnatural-historypipecolic acidorganic-acidsfood-intakemicemutationstext::journal::journal article::research article