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Huntington’s disease (HD) is a genetic, neurodegenerative condition that is characterized by progressive dementia and death within 10 to 15 years. This autosomal dominant disease, typified by choreic movements, can have onset at any age, but usually symptoms begin to occur in adulthood. There is currently no specific treatment of the disease, but dopamine antagonists phenothiazines and butyrophenones have been useful in controlling chorea.
A great deal of HD research has focused on the genetic aspects of the disease. The HD gene, located on the 4p16.3 chromosome, has been linked to the protein product, huntingtin, as well as an abnormal number of CAG nucleotide triplets in the genome of HD patients. While normal genomes consist of 11 to 34 repeat units of CAG nucleotides, HD patients have anywhere from 37 to 121 repeat units, depending on the age of onset and severity of the disease. More repeat units have been associated with earlier onset of the disease.
The neuronal loss found in all HD patients' brains is localized in the striatum, a brain structure involved in the control of motor, cognitive and psychoaffective behaviors. However, the pattern of degeneration of the striatum is topographic and selective for subpopulations of striatal neurons. For example, a portion of the striatum named the tail of the caudate nucleus is much more sensitive to degeneration than other striatal areas. Similarly, striatal neurons that project outside the striatum (so-called "spiny neurons") are more sensitive to degeneration than interneurons (so-called "aspiny neurons"), which have axons that remain inside the striatum. Over the past few years, many researchers have been trying to understand the selectively organized circuitry of the brain in the hope that it will contribute to the decipherment of the cause and pathogenesis of many neurodegenerative diseases like HD. Unfortunately, despite the large amount of work published on this issue, the mechanisms involved in the selective death of striatal neurons in HD still remain unknown.
One hypothesis of major interest in the scientific community which explains the neuronal death in many neurodegenerative diseases, including HD, is that of "excitotoxicity". According to this hypothesis, neurons die because they are "overexcited" by an abnormal release of glutamate, the most abundant excitatory neurotransmitter in the central nervous system. Researchers on HD have therefore focused much of their interest on glutamate and glutamate receptors based on the idea that neuronal death in the striatum of HD patients may be caused by loss of control of glutamate release.
Most of the glutamate in the striatum is provided by projections from the cerebral cortex which terminate mostly in striatal projection neurons. Glutamate mediates its excitatory effects via activation of different types of receptors located in the plasma membrane of striatal neurons. Recent data published in 1997 in Proceedings of the National Academy of Sciences USA by Rubinsztein and colleagues showed that variations in the genotypes of the GluR6 subunit, a protein involved in the composition of a glutamate receptor subtype named "Kainate receptors", are associated with changes in the age of onset of HD. These findings highlight the importance and the potential involvement of kainate receptors in HD pathogenesis.
Based on these data, the goal of our work was to localize the GluR6 protein in the striatum to understand better how it might mediate neuronal death in HD patients. Using antibodies raised against the GluR6 subunit, we visualized at the electron microscopic level the exact sites of localization of this protein in the monkey striatum. The most important data of our study are that the GluR6 subunit is expressed preferentially on the surface of axon terminals coming from the cerebral cortex, i.e. those terminals that release most of the glutamate in the striatum. This strongly suggests that the GluR6 subunit mutation in HD might result in an abnormal regulation of kainate receptors on cortical terminals, which eventually leads to an increase of glutamate release in the striatum and neuronal death by excitotoxicity.
The results of our study will be submitted for publication in the next few weeks. We are convinced that these findings will open up new research avenues regarding the potential implication of kainate receptors in HD pathogenesis. This may lead to the development of novel therapeutic strategies using drugs targeted to kainate receptors in Huntington's disease.
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