Brain Advance Access originally published online on January 30, 2006
Brain 2006 129(4):899-910; doi:10.1093/brain/awl009
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A diet-induced mouse model for glutaric aciduria type I
1 Department of Neurosurgery, 2 Department of Radiology, Center for NMR Research, 3 Department of Cellular and Molecular Physiology and Ophthalmology, Penn State College of Medicine, 4 Department of Pathology, 5 Department of Biochemistry and Molecular Biology, 6 Department of Pharmacology, Jake Gittlen Cancer Research Foundation, Hershey, PA and 7 Department of Pediatrics, University of Colorado Health Sciences Center, Denver, CO, USA
Correspondence to: Keith C. Cheng, Jake Gittlen Cancer Research Foundation, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA E-mail: kcheng{at}psu.edu
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.
Key Words: striatum; subarachnoid haemorrhage; animal model; blood–brain barrier; encephalopathy
Abbreviations: 3-OHGA = 3-hydroxyglutaric acid; BBB = blood–brain barrier; GA = glutaric acid; GA-1 = glutaric aciduria type I; GCDH = glutaryl-CoA dehydrogenase; GFAP = glial fibrillary acidic protein; OHGA = hydroxyglutaric acid; RITC = rhodamine isothiocyanate; WT = wild-type
Received October 6, 2005. Revised December 9, 2005. Accepted December 20, 2005.
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