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

TLDR

The cause of selective neuronal death in Huntington’s disease remains unknown, but evidence points to energetic defects and oxidative damage, including an interaction between huntingtin and the glycolytic enzyme GAPDH. The authors performed spectrophotometric assays on postmortem brain tissue to assess oxidative phosphorylation enzyme activities and oxidative damage markers (8‑hydroxydeoxyguanosine and superoxide dismutase) across basal ganglia and regions relatively spared by HD pathology. Complex II‑III activity was markedly reduced in HD caudate (−29 %) and putamen (−67 %), complex IV activity was reduced in the putamen (−62 %), while complex I and GAPDH activities were unchanged; 8‑hydroxydeoxyguanosine levels were elevated in caudate and cytosolic SOD activity was slightly reduced in parietal cortex and cerebellum, underscoring metabolic dysfunction and oxidative damage in HD.

Abstract

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 (OH 8 dG) in nuclear DNA, and superoxide dismutase (SOD) activity. OH 8 dG 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.