title: A diet-induced mouse model for glutaric aciduria type I.
abstract: In the autosomal recessive human disease, glutaric aciduria type I (GA-1), glutaryl-CoA dehydrogenase (GCDH) deficiency disrupts the mitochondrial catabolism of lysine and tryptophan. Affected individuals accumulate glutaric acid (GA) and 3-hydroxyglutaric acid (3-OHGA) in the serum and often suffer acute striatal injury in childhood. Prior attempts to produce selective striatal vulnerability in an animal model have been unsuccessful. We hypothesized that acute striatal injury may be induced in GCDH-deficient (Gcdh-/-) mice by elevated dietary protein and lysine. Here, we show that high protein diets are lethal to 4-week-old and 8-week-old Gcdh-/- mice within 2-3 days and 7-8 days, respectively. High lysine alone resulted in vasogenic oedema and blood-brain barrier breakdown within the striatum, associated with serum and tissue GA accumulation, neuronal loss, haemorrhage, paralysis, seizures and death in 75% of 4-week-old Gcdh-/- mice after 3-12 days. In contrast, most 8-week-old Gcdh-/- mice survived on high lysine, but developed white matter lesions, reactive astrocytes and neuronal loss after 6 weeks. Thus, the Gcdh-/- mouse exposed to high protein or lysine may be a useful model of human GA-1 including developmentally dependent striatal vulnerability.
authors.affiliation: Department of Neurosurgery, Penn State College of Medicine, Hershey, PA 17033, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Zinnanti
authors.forename: Jelena
authors.initials: J
authors.lastname: Lazovic
authors.forename: Ellen B
authors.initials: EB
authors.lastname: Wolpert
authors.forename: David A
authors.initials: DA
authors.lastname: Antonetti
authors.forename: Michael B
authors.initials: MB
authors.lastname: Smith
authors.forename: James R
authors.initials: JR
authors.lastname: Connor
authors.forename: Michael
authors.initials: M
authors.lastname: Woontner
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Goodman
authors.forename: Keith C
authors.initials: KC
authors.lastname: Cheng
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001812:Blood-Brain Barrier; D002199:Capillary Permeability / Q000187:drug effects; D003342:Corpus Striatum / Q000098:blood supply; D004032:Diet / Q000009:adverse effects*; D004044:Dietary Proteins / Q000008:administration & dosage / Q000633:toxicity*; D004195:Disease Models, Animal; D005260:Female; D005977:Glutarates / Q000494:pharmacology / Q000652:urine*; D008239:Lysine / Q000633:toxicity; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000473:pathology; D016019:Survival Analysis; D046509:Tissue Culture Techniques
chemical_list: C108959:3-hydroxyglutaric acid; D004044:Dietary Proteins; D005977:Glutarates; C035736:glutaric acid; D008239:Lysine