Biochemical abnormalities and excitotoxicity in Huntington's disease brain

Abstract

The physiological role of huntingtin and the mechanisms by which the expanded CAG repeat in ITI5 and its polyglutamine stretch in mutant huntingtin induce Huntington's disease (HD) are unknown. Several techniques have now demonstrated abnormal metabolism in HD brain; direct measurement of respiratory chain enzyme activities has shown severe deficiency of complex II/III and a milder defect of complex IV. We confirm that these abnormalities appear to be confined to the striatum within the HD brain. Analysis of complex II/III activity in HD fibroblasts was normal, despite expression of mutant huntingtin. Although glyceraldehyde 3‐phosphate dehydrogenase (a huntingtin binding protein) activity was normal in all areas studied, aconitase activity was decreased to 8% in HD caudate, 27% in putamen, and 52% in cerebral cortex, but normal in HD cerebellum and fibroblasts. We have demonstrated that although complexes II and III are those parts of the respiratory chain most vulnerable to inhibition in the presence of a nitric oxide (NO•) generator, aconitase activity was even more sensitive to inhibition. The pattern of these enzyme deficiencies and their parallel to the anatomical distribution of HD pathology support an important role for NO• and excitotoxicity in HD pathogenesis. Furthermore, based on the biochemical defects we have described, we suggest that NO• generation produces a graded response, with aconitase inhibition followed by complex II/III inhibition and the initiation of a self‐amplifying cycle of free radical generation and aconitase inhibition, which results in severe ATP depletion. We propose that these events are important in determining neuronal cell death and are critical steps in the pathogenesis of HD. Ann Neurol 1999;45:25–32

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).…”

“…Moreover, increased glucose metabolism and ATP levels were found in brain tissue of HD N171-82Q mice, suggesting that the neuronal damage in HD tissue may be associated with increased energy metabolism at the tissue level, leading to modified levels of various intermediary metabolites (Olah et al, 2008). A decrease in mitochondrial complexes II-III activity and a decrease in succinate oxidation were also found in striatal tissue from HD patients (Schapira, 1998;Tabrizi et al, 1999). 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).…”

Mitochondrial dysfunction in Parkinson's disease

“…Severe defects of complexes II and III of the respiratory chain have also been described in Huntington's disease brain. 92,93 The relevance of the latter has been highlighted by the recent observation that mutant huntington reduces the expression of the peroxisome proliferator-activated receptor-g co-activator 1a (PGC-1a). 94 .…”

Selective defect of in vivo glycolysis in early Huntington's disease striatum

“…Although it is now known that an expansion of the triple repeat CAG in the IT15 gene on chromosome 4 leads to production of an abnormal polyglutamine string on the huntingtin protein, it is still unclear how this leads to selective neuronal cell death (1). In postmortem specimens from the striatum of patients with HD, reduced activity of the mitochondrial electron transport system (ETS) (29-76% decreases in complexes II and III and 30-62% decreases in complex IV) has been measured in vitro, although these findings have not been universal (2)(3)(4)(5)(6). These findings and the correlative effects of mitochondrial toxins in producing striatal neuronal loss in animal models suggest that excitotoxicity triggered by reduced ATP production as a consequence of impaired mitochondrial oxidative phosphorylation may be an important mechanism for neuronal death in HD (7).…”