The role of protein aggregation in Huntington's disease.
Year: 2010
Type: dissertation
Abstract: Huntington’s disease (HD) is a hereditary progressive neurodegenerative\ndisorder characterised by chorea, general motor impairment, psychiatric\ndisturbances and dementia, leading to death within 10 to 20 years of onset.\nIt is caused by a (CAG)n trinucleotide repeat expansion in the gene IT15\nthat is translated into a prolonged polyglutamine tract in the protein huntingtin.\nThis mutation leads to the self-association of huntingtin to form aggregates in\nthe brains of affected people.\nWork in Professor Nicotera’s group at the MRC Toxicology Unit identified\nexpression changes in Rab11, a protein involved in endosomal recycling, in a\ncell culture model of HD. The aim of this thesis was to investigate whether\nendosomal recycling is affected in this model. Monitoring the trafficking of\nlabelled transferrin by Western blotting and live-cell imaging showed rapid\nuptake of transferrin into all cells, but a significantly reduced rate of clearance in\ncells containing huntingtin aggregates, which was associated with the\naccumulation of transferrin in the endosomal recycling compartment (ERC).\nThis finding demonstrates an aggregate-specific lesion in the exit of cargo from\nthe ERC in the absence of cell death. As endosomal recycling is essential for\ncorrect neuronal function, this process provides a mechanism whereby protein\ninclusions may contribute to the cognitive and motor deficits seen in HD.\nA second project focused on purification of aggregates to determine if they\ncould sequester material important for cellular function. Many attempts to purify\nthe aggregates in their intact globular form revealed their highly unspecific\naffinity towards other proteins, which renders purification methods very\nsusceptible to artefacts. The large globular aggregates could, however, be\ndispersed by SDS-treatment into fibrils of approximately 10 nm diameter, which\nwere subsequently purified and visualised by electron microscopy.
Author: Claire Didszun
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W844660510