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 ( 1 H 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.

The Human Gene SLC25A29, of Solute Carrier Family 25, Encodes a Mitochondrial Transporter of Basic Amino Acids

“…However, with the exception of the carnitine/acylcarnitine carrier, which catalyzes both uniport and exchange in vivo, the phosphate and glutamate carriers and most likely SLC25A29 mediate only uniport physiologically because the exchanges they may operate are nonproductive. Of note, the specific activity of reconstituted SLC25A29 is comparable with the activities of other SLC25 proteins (19,23,41,42), and the K m values of arginine and lysine for SLC25A29 are lower or not much higher than their cytosolic concentrations (43,44).…”

Identification of the 2-Hydroxyglutarate and Isovaleryl-CoA Dehydrogenases as Alternative Electron Donors Linking Lysine Catabolism to the Electron Transport Chain ofArabidopsisMitochondria

“…While the process of Lys degradation is not, as yet, fully understood, a range of important studies in plants and mammals precede our work (Galili et al, 2001;Mills et al, 2006;Stepansky et al, 2006;Zinnanti et al, 2007;Angelovici et al, 2009;Struys and Jakobs, 2010). Current knowledge of mammalian Lys catabolism is largely based on a range of studies in different species in which [ 14 C]-labeled Lys was supplied as tracer (Ghadimi et al, 1971;Chang, 1982).…”

Experimental evidence that bioenergetics disruption is not mainly involved in the brain injury of glutaryl-CoA dehydrogenase deficient mice submitted to lysine overload

“…Glutaryl-CoA dehydrogenase deficient mice (GcdhÀ/À ) had increased cerebral, blood and urine GA and 3HGA levels and displayed vacuolation in the frontal cortex (spongiform leukoencephalopathy). Exposing these mice to a high protein or Lys chow provoked neuronal loss, myelin disruption and gliosis, mostly in the striatum and deep cortex, and induced higher brain GA concentrations indicating GA formation from Lys catabolism in this tissue (Zinnanti et al, 2006(Zinnanti et al, , 2007.…”

“…Neurological symptoms including developmental delay, dystonia, dyskinesia, hypotonia, seizures and spasticity begin especially after the encephalopathic crises commonly found in these patients (Hoffmann and Zschocke, 1999;Neumaier-Probst et al, 2004). Excitotoxicity Kolker et al, 1999Kolker et al, , 2002aKolker et al, , 2002bKolker et al, , 2004Lagranha et al, 2014;Magni et al, 2009;Porciuncula et al, 2000Porciuncula et al, , 2004Rosa et al, 2004Rosa et al, , 2007Wajner et al, 2004), oxidative stress (de Oliveira Marques et al, 2003;Fighera et al, 2006;, 2005bMagni et al, 2007;Seminotti et al, 2013) and mitochondrial dysfunction (da et al, 2005;Ferreira Gda et al, 2005Latini et al, 2005a;Olivera et al, 2008;Sauer et al, 2005;Silva et al, 2000;Zinnanti et al, 2007) have been associated with the pathogenesis of the brain injury in GA I, but the contribution of each pathomechanism is still under debate and needs further investigation (Jafari et al, 2011).…”