Tabrizi, et al. have made very important contributions to the conquest of HD.
The language of the following abstract is in contrast to the language of much HD research. They say, "We confirm ..." and "We have demonstrated...". It is not the usual "maybe or suggests".
The subject cell part of the abstract is the mitochondria. Mitochondria produce a small molecule called ATP (adenosine triphosphate). The utility of ATP lies in two unstable bonds that release energy. ATP is identical to the adenine (A as in CAG) nucleotide in RNA except for two extra phosphate groups.
Mitochondria are much like bacteria and a single cell can have a large population of mitochondria. The number of mitochondria in a single cell is in proportion to the energy requirement of the the host cell. A single neuron has many hundreds of mitochondria. ATP is the source of most all of our energy. We produce more than our weight of ATP every day.
The abstract talks of complexes with roman numerals. These are the stages in the manufacture of ATP by our mitochondria. The input for the complexes is called the Krebs or citric acid cycle. Aconitase is an up front catalyst of the citric acid cycle that acts on citric acid (like from an orange).
The abstract provides support for the idea that the cause and progression of HD are by two different
mechanisms. HD pathology is now corolated with an enzyme of known function. At long last the pieces of the HD puzzle are beginning to fit.--Jerry 01/24/99
Ann Neurol 1999 Jan;45(1):25-32. Tabrizi SJ, et al.
| "We propose that these events are important in determining neuronal cell death and are critical steps in the pathogenesis of HD." |
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.