Zinnanti, William J. and Lazovic, Jelena (2010) Mouse model of encephalopathy and novel treatment strategies with substrate competition in glutaric aciduria type I. Molecular Genetics and Metabolism, 100 (Supple). S88-S91. ISSN 1096-7192 http://resolver.caltech.edu/CaltechAUTHORS:20100519-114137851
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Glutaric aciduria type I (GA-1) results from an inherited defect in a common step of lysine, hydroxylysine and tryptophan metabolism. This defect is associated with an age-dependent susceptibility to encephalopathy commonly preceded by non-specific childhood illnesses or fasting. The brain injury that develops with encephalopathic crisis in GA-1 is anatomically and symptomatically similar to Huntington’s disease, affecting the striatum. The mechanism of injury remains poorly understood. Recently, an animal model of GA-1 encephalopathy was developed by providing GA-1 mice with added dietary lysine. This model shows age-dependent susceptibility similar to the human disease. Enhanced lysine accumulation and utilization in the immature brain correlates with increased glutaric acid levels and age-dependent susceptibility. Neurotransmitter and Krebs cycle intermediate depletion in this model represent novel findings toward uncovering the mechanism of neuronal injury. Additionally this mouse model is responsive to glucose analogous to human GA-1 and provides insight toward the mechanism of this effect. Together these findings led to a new treatment strategy of competing with brain lysine uptake that shows promising results. This research serves as a model for understanding blood brain barrier amino acid transport at critical stages of development and may help advance understanding of brain injury and development of treatments in other IEMs including urea cycle disorders.
|Additional Information:||© 2010 Elsevier. Received 25 January 2010; accepted 22 February 2010. Available online 1 March 2010.|
|Subject Keywords:||Glutaric aciduria; Metabolic encephalopathy; Mouse model|
|Usage Policy:||No commercial reproduction, distribution, display or performance rights in this work are provided.|
|Deposited By:||Jason Perez|
|Deposited On:||20 May 2010 20:05|
|Last Modified:||26 Dec 2012 12:03|
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