Oxidative damage and metabolic dysfunction in Huntington's disease: Selective vulnerability of the basal ganglia

Abstract

The etiology of the selective neuronal death that occurs in Huntington's disease (HD) is unknown. Several lines of evidence implicate the involvement of energetic defects and oxidative damage in the disease process, including a recent study that demonstrated an interaction between huntingtin protein and the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Using spectrophotometric assays in postmortem brain tissue, we found evidence of impaired oxidative phosphorylation enzyme activities restricted to the basal ganglia in HD brain, while enzyme activities were unaltered in three regions relatively spared by HD pathology (frontal cortex, parietal cortex, and cerebellum). Citrate synthase-corrected complex II-III activity was markedly reduced in both HD caudate (-29%) and putamen (-67%), and complex IV activity was reduced in HD putamen (-62%). Complex I and GAPDH activities were unaltered in all regions examined. We also measured levels of the oxidative damage product 8-hydroxydeoxyguanosine (OH8dG) in nuclear DNA, and superoxide dismutase (SOD) activity. OH8dG levels were significantly increased in HD caudate. Cytosolic SOD activity was slightly reduced in HD parietal cortex and cerebellum, whereas particulate SOD activity was unaltered in these regions. These results further support a role for metabolic dysfunction and oxidative damage in the pathogenesis of HD.

Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington’s disease knock-in striatal cells

“…An increase in SOD activity was previously observed in R6/1 HD mice at 19 weeks of age, although older mice exhibited decreased SOD activity [70]. Reduced activity of SOD1 was also observed in cortex and cerebellum of post-mortem human brain tissues [7] and in erythrocytes [5] of HD patients. In a previous study we demonstrated increased ROS levels and decreased GCL activity, despite increased glutathione levels in HD striatal cells, which occurred as a result of a lower capacity of multidrug resistance-associated protein 1 (Mrp1) to export GSH to the extracellular space [17].…”

Bioenergetic dysfunction in Huntington's disease human cybrids

“…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).…”

FK506 prevents mitochondrial-dependent apoptotic cell death induced by 3-nitropropionic acid in rat primary cortical cultures

“…Several studies have reported the occurrence of mitochondrial dysfunction in brains from Huntington disease (HD) patients, namely, through the inhibition of respiratory chain complexes II and III (Browne et al, 1997;Gu et al, 1996). Systemic administration of the mitochondrial toxin 3-nitropropionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase, was shown to elicit behavioral abnormalities and cortical and striatal neuronal degeneration in rats and nonhuman primates, similar to that seen in humans with HD (Beal et al, 1993;Brouillet et al, 1998).…”