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Molecular investigations in animal models of Huntington's disease

Gilder, Michael Frederick James; (1999) Molecular investigations in animal models of Huntington's disease. Doctoral thesis , UCL (University College London). Green open access

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NF-κB is a transcription factor family, which includes the proteins p65, p50 and p52. Inducible in most cell types, NF-κB (p65) has been demonstrated to be present in the nuclei of cortical neurones. This work demonstrates that p65, p50 and p52 are also present in striatal neurones, and that p52 localises to neuronal nuclear bodies. Administration of the excitotoxin quinolinic acid (QA) or the glial activator ciliary neurotrophic factor (CNTF) leads to an increase of protein binding to NF-κB DNA oligonucleotides in a biphasic temporal manner. PAGE revealed no significant change in expression of known NF-κB proteins after either treatment, but a 35 kD protein of unknown identity is recognised by anti-p50, being transiently expressed following both QA and CNTF administration. Furthermore, p52 and p65 can be localised within glial cells following QA treatment. Endogenous levels of striatal CNTF are also seen to increase significantly at 168 hours post-lesion. These results implicate NF-κB in the regulation of the glial response to striatal lesion. Polyglutamine repeats can bind via hydrogen bonding in vitro, and may lead to aggregation of proteins if mutation leads to increased trinucleotide repeat length. A preliminary study of the DNA binding, expression and localisation of the polyglutamine repeat transcription factors Brain-2 (BRN-2), glucocorticoid receptor and TATA binding protein (TBP) were investigated in the CNS of R6/2 transgenic mice expressing abnormal huntingtin protein (htt) possessing expanded polyglutamine repeats. These mice develop neuronal nuclear inclusions of aggregated htt and demonstrate symptoms similar to juvenile onset Huntington's disease. Increased protein binding to OCT consensus site DNA was found in the cortex of transgenes corresponding to BRN-2. This work provides no evidence that abnormal htt induces symptoms via transcriptional dysregulation, as has been proposed. However, decreased expression of BRN-2 is seen in the hypothalamic paraventricular nucleus in transgenic animals.

Type: Thesis (Doctoral)
Title: Molecular investigations in animal models of Huntington's disease
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10120596
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