Bannister, L-J.; (2004) An ultrastructural and molecular analysis of neuronal degeneration in Huntington's disease. Doctoral thesis , University of London.

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Abstract

Huntington's disease (HD) is an inherited, progressive, neurodegenerative disorder for which there is no effective treatment. It is one of nine disorders known to be caused by the expansion of a genomic CAG repeat sequence, producing a protein with an expanded array of polyglutamine residues. The mechanisms underlying the degeneration and death of neurons in HD remain unclear, and are the subjects of this investigation. Several animal models have been generated to investigate the pathogenic mechanisms underlying HD, of which this thesis uses two: the Bates R6/2 mouse, which has the affected region of the human gene inserted into its genome; and the Shelboume Hdh 'knock-in' mice, in which the CAG repeat sequence of the murine huntingtin gene homologue has been expanded into the pathogenic range. Ultrastructural analyses have been undertaken on the CNS from each of the mouse models, detailing the subcellular changes that occur. This has been furthered by analyses of the molecular machinery of apoptosis in an attempt to identify factors involved in neurodegeneration. Affected neurons in each of the HD models, and in aged wild-type mice, exhibit very similar morphologies: a condensation of cytoplasm and nucleoplasm, disturbances in the nuclear membrane, dilation and disruption of cell organelles and increased autophagic activity. These morphologic changes do not correlate with those reported to occur during apoptosis. Furthermore, molecular analyses reveal the involvement of none of the components of apoptosis. In relating each of the mice, it is clear that neurodegenerative changes do not correlate with phenotypic changes; rather the early and most pronounced symptoms of HD are a result of neuronal dysfunction. It is also concluded that the increased autophagic activity and cell condensation occur in adult neurons under stress and thus may be indicative of a common process by which adult neurons die.

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