Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I
| Autor: | Keith C. Cheng, Stephen I. Goodman, Ian A. Simpson, Russell E. Jacobs, James P. O'Callaghan, Michael Woontner, Jelena Lazovic, Cathy Housman, James R. Connor, William J. Zinnanti, Kathryn F. LaNoue |
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| Rok vydání: | 2007 |
| Předmět: |
Aging
medicine.medical_specialty Glutamic Acid Glutaryl-CoA dehydrogenase Context (language use) Mitochondrion Biology Glutaric acid gamma-Aminobutyric acid Glutarates Mice chemistry.chemical_compound In vivo Internal medicine medicine Animals Humans Genetic Predisposition to Disease Child Amino Acid Metabolism Inborn Errors Nuclear Magnetic Resonance Biomolecular gamma-Aminobutyric Acid Mice Knockout Neurons Glutaryl-CoA Dehydrogenase Lysine Tryptophan Glutamate receptor Brain Diseases Metabolic Inborn General Medicine Glutamic acid Homoarginine Diet Mitochondria Disease Models Animal Glucose Endocrinology chemistry Caltech Library Services Research Article medicine.drug |
| Zdroj: | Journal of Clinical Investigation. 117:3258-3270 |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/jci31617 |
| Popis: | Glutaric acidemia type I (GA-I) is an inherited disorder of lysine and tryptophan metabolism presenting with striatal lesions anatomically and symptomatically similar to Huntington disease. Affected children commonly suffer acute brain injury in the context of a catabolic state associated with nonspecific illness. The mechanisms underlying injury and age-dependent susceptibility have been unknown, and lack of a diagnostic marker heralding brain injury has impeded intervention efforts. Using a mouse model of GA-I, we show that pathologic events began in the neuronal compartment while enhanced lysine accumulation in the immature brain allowed increased glutaric acid production resulting in age-dependent injury. Glutamate and GABA depletion correlated with brain glutaric acid accumulation and could be monitored in vivo by proton nuclear magnetic resonance (1H NMR) spectroscopy as a diagnostic marker. Blocking brain lysine uptake reduced glutaric acid levels and brain injury. These findings provide what we believe are new monitoring and treatment strategies that may translate for use in human GA-I. |
| Databáze: | OpenAIRE |
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