Remarkable progress has been since isolation of the Huntington's disease (HD) defect, with a rapid expansion of the knowledge concerning the HD gene, the huntingtin protein, related CAG repeat disorders, and potential mechanisms of pathogenesis. The process of HD pathogenesis appears to have two critical determinants: a novel physical property conferred on mutant huntingtin by polyglutamine, which triggers pathogenesis, a characteristic of the huntingtin protein that establishes the specificity of neuronal vulnerability. We have presented evidence, in the context, of an amino-terminal fragment, the altered vulnerability. We have presented evidence that, in the context, of an amino-terminal fragment, the altered physical property promotes self-aggregation in vitro with a threshold and progressivity for polyglutamine length strikingly similar to the human disorder. However, in HD patients, the novel property might well act at the level of full-length huntingtin, not necessarily by initially generating visible aggregates. This novel property of polyglutamine is likely to be the common element in the neuronal death displayed by the other CAG neurodegenerative disorders, but a second element, determined by the host protein, is clearly required to explain the specificity of neuronal loss in each disease. In the renewal period, we aim to investigate both elements of HD pathogenesis. To examine the polyglutamine component, we more precisely define the altered behavior of mutant huntingtin using atomic force microscopy and other assays, identify reagents capable of modifying it, and define the constituents the using atomic microscopy and other assays, identify reagents capable of modifying it, and define the constituents of soluble and insoluble huntingtin complexes from HD brain. To explore the specificity component, we will characterize the normal function of huntingtin to place it within a biochemical pathway using the powerful genetic tools that can be applied to the Drosophila HD homologue. As it has been since the discovery of the HD gene and its mutation, over overall goal remains the delineation of the steps that trigger the HD disease pathway in order to achieve a detailed understanding of pathogenesis, and to target specific processes for the development of rational therapies for treating this devastating disorder.
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