Disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG expansion on the HD gene on chromosome 4, which gives rise to an expanded polyglutamine (polyQ) tract in the huntingtin protein. HD is characterised primarily by motor abnormalities, but is also commonly associated with cognitive impairments and psychiatric disturbances. Huntingtin (HTT) dynamically shuttles between subcellular compartments, however the mutant huntingtin protein (mHTT) is mislocalised to cell nuclei, where it may interfere with nuclear functions, such as transcription. The phosphorylation of HTT has been implicated with the regulation of its subcellular localisation; however the mechanism by which the mislocalisation of mHTT occurs is currently unknown. The localisation of HTT in an immortalised embryonic striatal cell model of HD (StHdhQ111) was identified as being more nuclear with a longer polyQ length. Additionally, stimulation of StHdhQ111 lines with a panel of growth factors alters the apparent subcellular localisation of HTT in a polyQ length-dependent manner. Aberrant kinase responses to growth factor stimulation were identified by ELISA assay. Inhibition of AKT1 and MEK1 phosphorylation indicated that their activation may be involved in mHTT mislocalisation and immediate-early gene expression. Transcriptional dysregulation is a characteristic feature of HD pathogenesis that may be directly influenced by HTT localisation. Microarray analysis of differential gene expression responses to growth factor stimulation uncovered a potential role for SMAD transcription factor activity and the transforming growth factor-β pathway in HD pathogenesis. Primary embryonic striatal cells from the HdhQ111 and HdhQ150 mouse models of HD showed similarities to the StHdhQ111 cell model in terms of HTT localisation, kinase signalling and gene expression. Cellular dysfunction may therefore be an early HD phenotype that is present from embryogenesis, and potentially alters HD development and progression; aberrant control of kinase signalling may regulate mHTT mislocalisation, which in turn modulates transcriptional dysregulation and contributes to HD pathogenesis.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:590321 |
| Date | January 2013 |
| Creators | Bowles, Kathryn R. |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/56396/ |
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