Increased Vulnerability to 3‐Nitropropionic Acid in an Animal Model of Huntington's Disease

Abstract

There is substantial evidence for both metabolic dysfunction and oxidative damage in Huntington's disease (HO). In the present study, we used in vivo microdialysis to measure the conversion of 4-hydroxybenzoic acid to 3,4-dihydroxybenzoic acid (3,4-DHBA) as a measure of hydroxyl radical production in a transgenic mouse model of HO, as well as in littermate controls. The conversion of 4-hydroxybenzoic acid to 3,4-DHBA was unchanged in the striatum of transgenic HO mice at baseline. Following administration ofthe mitochondrial toxin 3-nitropropionic acid (3-NP), there were significant increases in 3,4-DHBA generation in both control and transgenic HD mice, and the increases in the transgenic HO mice were significantly greater than those in controls. Furthermore, administration of 3-NP produced significantly larger striatal lesions in transgenic HO mice than in littermate controls. The present results show increased sensitivity to the mitochondrial toxin 3-NP in transgenic HD mice, which suggests metabolic dysfunction in this mouse model of HO. Key Words: Huntington's disease-3-Nitropropionic acid-Free radicals-Oxidative damage-Transgenic mice-Mitochondna. J. Neurochem. 71, 2642-2644 (1998).Huntington's disease (HD) is a prototypical autosomal dominant neurodegenerative disease typified by selective basal ganglia degeneration. The HD gene mutation was shown to be an expansion of a trinucleotide repeat in the coding region of an unknown protein termed huntingtin (Huntington's Disease Collaborative Research Group, 1993). The gene product is widely distributed in both neurons and extraneuronal tissue, but the means by which it leads to neuronal degeneration remains obscure. We suggested that the genetic defect may lead to impaired oxidative phosphorylation, which may play a critical role in pathogenesis. We and others found a decrease in mitochondrial complex 11-111 activity in HD basal ganglia (Gu et al., 1996;Browne et al., 1997). Furthermore, using MRI spectroscopy, we found increased lactate levels within the HD cerebral cortex and in basal ganglia, as well as an increase in phosphocreatine to inorganic phosphate ratio in HD resting muscle (Koroshetz et al., 1997;Jenkins et al., 1998).We previously demonstrated that systemic administration of the irreversible succinate dehydrogenase inhibitor 3-nitropropionic acid (3-NP) leads to selective striatal lesions, which are associated with increased oxidative damage (Beal et al., 1993 Schulz et al., 1995a,b). A breakthrough in HD research is the development of transgenic mouse models made by overexpression of 115-150 CAG repeats in an Nterminal fragment of exon-1 of huntingtin (Mangiarini et al., 1996). Transgenic mice with one copy corresponding to 150 repeats (R6 /2) show choreiform movements, involuntary stereotypic movements, tremor, and epileptic seizures. The mice stop gaining weight at 6 weeks of age and show progressive weight loss starting at 7 weeks of age, despite apparently increased caloric intake. The mice develop intranuclear inclusion bodies and...

Mitochondrial Cyclic AMP Response Element-binding Protein (CREB) Mediates Mitochondrial Gene Expression and Neuronal Survival

“…One such naturally occurring plant toxin, 3-nitropropionic acid (3-NP), is an irreversible inhibitor of succinate dehydrogenase and both the Krebs cycle and complex II activity of the electron transport chain (19). 3-NP is associated with HD-like symptoms in both humans and animals and, as such, has been used as an experimental model for HD (20). We further hypothesized that mitochondria may be more susceptible to mitochondrial toxins in the presence of a dominant negative or mutant mitochondrial CREB.…”

Mitochondrial Respiration and ATP Production Are Significantly Impaired in Striatal Cells Expressing Mutant Huntingtin

“…There have been several reports suggesting altered sensitivity of transgenic HD mice to malonate or 3-NP (41)(42)(43). Also, a previous study from our laboratory showed that striatal cells expressing mutant huntingtin were more sensitive than wildtype cells to 3-NP induced toxicity, but not to rotenone treatment (17).…”

“…of six independent experiments. huntingtin-induced alterations in the mitochondrial ATP-sensitive K ϩ channel could explain the decreased ⌿m and calcium retention capacity reported in several HD models (13), as well as the altered sensitivity of transgenic HD mice to malonate or 3-NP (41)(42)(43). Our future studies will be directed toward examining this possibility.…”

Abnormalities of Neurogenesis in the R6/2 Mouse Model of Huntington's Disease Are Attributable to theIn VivoMicroenvironment

“…It has been shown previously that transgenic HD mice are resistant to excitotoxic lesions (Hansson et al, 1999(Hansson et al, , 2001aHickey and Morton, 2000;Petersen et al, 2001;MacGibbon et al, 2002), although this is age, strain, and excitotoxin dependent (Bogdanov et al, 1998;Hansson et al, 2001a;Petersen et al, 2002;Schauwecker, 2002;Zeron et al, 2002). QA has been used in various doses to induce lesions in mice [1 l of 8, 20, and 30 nmol (Zeron et al, 2002;Hansson et al, 2001b;Petersen et al, 2002, respectively], so, in the present study, a larger dose (40 nmol) was given to all animals in an attempt to induce a lesion in R6/2 mice.…”