Jolly, R.S.; (2008) The ubiquitin proteasome system in Huntington's disease. Doctoral thesis , University of London.

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Abstract

Huntington's disease (HD) is an autosomally dominant, progressive movement disorder, caused by an expansion in the polyglutamine tract of huntingtin protein. HD is pathologically characterised by the presence of insoluble, proteinaceous neuronal intranuclear inclusions (NHs) and dystrophic neurite inclusions (DNIs) in affected neurons that can be immunostained for ubiquitin and other proteins involved in the ubiquitin-proteasome system (UPS). The UPS is a highly conserved mechanism for degradation of both normal and misfolded proteins in eukaryotic cells. This has led to suggestions that the UPS is inhibited in HD. This study utilises microscopy, biochemistry and fluorometric assays to examine the molecular composition of aggregates and the potential dysfunction of the UPS in the R6/2 mouse line, an established model of HD. The ultrastructure of aggregates is shown to be predominantly amorphous and granular in appearance and likely to be formed through the process of transglutamination. Immunohistochemical data shows that certain chaperones, ubiquitin-like proteins (UBLs) and proteins involved in the UPS localise to Nils and DNIs differentially. Fluorometric assays demonstrate that the proteasome exhibits a differential profile in R6/2 mice where both chymotrypsin-like and PGPH-like activities are markedly increased whilst trypsin-like activity is decreased relative to litter-mate control mice. Furthermore, these activity changes may be explained by alterations in proteasome regulation, levels and maturation. These results suggest that, in the R6/2 line, the proteasome is not inhibited by the presence of mutant huntingtin, rather that there are alterations of the catalytic activities of the proteasome. It appears that Nil's act not only as focal points of proteolysis, but also of proteasome biogenesis. This is consistent with, and extends, the concept of clastosomes.

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