Mitochondrial defect in Huntington's disease caudate nucleus

Gu, Muxin; Gash, M. T.; Mann, Vincent M.; Javoy‐Agid, F.; Cooper, Jonathan M.; Schapira, Anthony H.V.

doi:10.1002/ana.410390317

Cited by 676 publications

(433 citation statements)

References 17 publications

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“…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).…”

supporting

confidence: 67%

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

Богданов

Ferrante

Kuemmerle

et al. 1998

Journal of Neurochemistry

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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...

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supporting

confidence: 67%

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

Богданов

Ferrante

Kuemmerle

et al. 1998

Journal of Neurochemistry

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“…Accordingly, the expression of two subunits of the complex II is decreased in the striatum of HD patients, affecting the dehydrogenase activity of the complex (Benchoua et al, 2006). A small decrease in complex IV in brain samples was also reported (Browne et al, 1997;Gu et al, 1996;Schapira, 1998;Tabrizi et al, 1999).…”

Section: Introductionmentioning

confidence: 82%

“…In platelets from HD patients, some authors found a decrease in complex I activity (Parker et al, 1990), whereas others reported no changes in the activity of mitochondrial complexes (Gu et al, 1996;Powers et al, 2007a). Moreover, the phosphocreatine/ inorganic phosphate ratio was significantly decreased in resting muscle (Koroshetz et al, 1997) of HD patients, evidencing bioenergetic changes in HD peripheral tissues.…”

Section: Introductionmentioning

confidence: 97%

Bioenergetic dysfunction in Huntington's disease human cybrids

Ferreira¹,

Cunha‐Oliveira²,

Nascimento³

et al. 2011

Experimental Neurology

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In this work we studied the mitochondrial-associated metabolic pathways in Huntington's disease (HD) versus control (CTR) cybrids, a cell model in which the contribution of mitochondrial defects from patients is isolated. HD cybrids exhibited an interesting increase in ATP levels, when compared to CTR cybrids. Concomitantly, we observed increased glycolytic rate in HD cybrids, as revealed by increased lactate/pyruvate ratio, which was reverted after inhibition of glycolysis. A decrease in glucose-6-phosphate dehydrogenase activity in HD cybrids further indicated decreased rate of the pentose-phosphate pathway. ATP levels of HD cybrids were significantly decreased under glycolysis inhibition, which was accompanied by a decrease in phosphocreatine. Nevertheless, pyruvate supplementation could not recover HD cybrids' ATP or phosphocreatine levels, suggesting a dysfunction in mitochondrial use of that substrate. Oligomycin also caused a decrease in ATP levels, suggesting a partial support of ATP generation by the mitochondria. Nevertheless, mitochondrial NADH/NAD t levels were decreased in HD cybrids, which was correlated with a decrease in pyruvate dehydrogenase activity and protein expression, suggesting decreased tricarboxylic acid cycle (TCA) input from glycolysis. Interestingly, the activity of alpha-ketoglutarate dehydrogenase, a critical enzyme complex that links the TCA to amino acid synthesis and degradation, was increased in HD cybrids. In accordance, mitochondrial levels of glutamate were increased and alanine was decreased, whereas aspartate and glutamine levels were unchanged in HD cybrids. Conversely, malate dehydrogenase activity from total cell extracts was unchanged in HD cybrids. Our results suggest that inherent dysfunction of mitochondria from HD patients affects cellular bioenergetics in an otherwise functional nuclear background.

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“…*Po0.05, **Po0.01 versus control myoblasts changes reported by morphological analyses of human HD skeletal muscle. 8 Previous reports have described altered mitochondrial oxidative metabolism in brain and peripheral tissues of HD subjects [6][7][8][9]19 and increased mitochondrial depolarization after stress conditions in both fibroblasts and lymphoblasts from HD subjects. 20,21 In our cell model, we observed mitochondrial DC m dissipation and cytochrome c release even under normal growth conditions.…”

Section: Discussionmentioning

confidence: 99%

Increased apoptosis, huntingtin inclusions and altered differentiation in muscle cell cultures from Huntington's disease subjects

et al. 2006

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Mutated huntingtin (htt) is ubiquitously expressed in tissues of Huntington's disease (HD) patients. In the brain, the mutated protein leads to neuronal cell dysfunction and death, associated with formation of htt-positive inclusions. Given increasing evidence of abnormalities in HD skeletal muscle, we extensively analyzed primary muscle cell cultures from seven HD subjects (including two unaffected mutation carriers). Myoblasts from presymptomatic and symptomatic HD subjects showed cellular abnormalities in vitro, namely mitochondrial depolarization, cytochrome c release, increased caspase-3, -8, and -9 activities, and defective cell differentiation. Another notable feature was the formation of htt inclusions in differentiated myotubes. This study helps to advance current knowledge about the downstream effects of the htt mutation in human tissues. Further applications may include drug screening using this human cellular model.

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Mitochondrial defect in Huntington's disease caudate nucleus

Cited by 676 publications

References 17 publications

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

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

Bioenergetic dysfunction in Huntington's disease human cybrids

Increased apoptosis, huntingtin inclusions and altered differentiation in muscle cell cultures from Huntington's disease subjects

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