Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I
William J. Zinnanti, … , Russell E. Jacobs, Keith C. Cheng
William J. Zinnanti, … , Russell E. Jacobs, Keith C. Cheng
Published October 11, 2007
Citation Information: J Clin Invest. 2007;117(11):3258-3270. https://doi.org/10.1172/JCI31617.
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Research Article Neuroscience

Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I

Abstract

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.

Authors

William J. Zinnanti, Jelena Lazovic, Cathy Housman, Kathryn LaNoue, James P. O’Callaghan, Ian Simpson, Michael Woontner, Stephen I. Goodman, James R. Connor, Russell E. Jacobs, Keith C. Cheng

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Figure 1

Neuronal localization of Gcdh expression (β-gal).

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Neuronal localization of Gcdh expression (β-gal). Motor ...
Motor cortex of WT (A) and Gcdh–/+ mouse (B) shows positive β-gal (green) staining colocalizes (yellow) with neurons (red) in layer V and VI of Gcdh–/+ mouse and not WT by immunofluorescence confocal microscopy. CA1 hippocampus from WT (C) and Gcdh–/+ mouse (D) shows positive β-gal staining for Gcdh–/+ mouse neurons only, similar to that found in motor cortex. Arrows indicate color change. (E) Average projection of 10 confocal slices through the CA1 hippocampus of a Gcdh–/+mouse shows no β-gal staining in endothelial cells (thin arrow) or astrocytes (red) (thick arrows). (F) A single slice through the CA1 hippocampus shows that nuclei associated with astrocytes (thick arrows) and endothelial cells (thin arrow) do not stain positive for β-gal while large nuclei of neurons are positively stained. β-Gal labeling is nuclear due to nuclear localizing sequence; see Methods. (A–D) β-Gal, green; NeuN, red; colocalization β-gal and NeuN, yellow; and DAPI, blue. Scale bars: 10 μm. (E and F) β-Gal, green; GFAP, red; and DAPI, blue. Scale bars: 10 μm.