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Brain Advance Access published online on January 30, 2006
Brain, doi:10.1093/brain/awl009
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© The Author (2006). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received October 6, 2005
Revised December 9, 2005
Accepted December 20, 2005

Article

A diet-induced mouse model for glutaric aciduria type I

William J. Zinnanti 1, Jelena Lazovic 2, Ellen B. Wolpert 3, David A. Antonetti 3, Michael B. Smith 2, James R. Connor 1, Michael Woontner 4, Stephen I. Goodman 4, and Keith C. Cheng 5 *

1 Department of Neurosurgery, Center for NMR Research, USA
2 Department of Radiology, Center for NMR Research, USA
3 Department of Cellular and Molecular Physiology and Ophthalmology, Penn State College of Medicine, USA
4 Department of Pediatrics, University of Colorado Health Sciences Center, Denver, CO, USA
5 Department of Pathology, Jake Gittlen Cancer Research Foundation, Hershey, PA, USA; Department of Biochemistry and Molecular Biology, Jake Gittlen Cancer Research Foundation, Hershey, PA, USA; Department of Pharmacology, Jake Gittlen Cancer Research Foundation, Hershey, PA, USA

* To whom correspondence should be addressed.
Keith C. Cheng, E-mail: kcheng{at}psu.edu


  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.

Keywords: striatum; subarachnoid haemorrhage; animal model; blood-brain barrier; encephalopathy.
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