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Title: Myeloid cell function in Huntington's disease
Author: Traeger, U.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2013
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Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene. The peripheral innate immune system contributes to HD pathogenesis and has been targeted successfully to modulate disease progression, but mechanistic understanding relating this to mutant (m)HTT expression in immune cells has been lacking. This thesis demonstrates that human HD myeloid cells produce excessive inflammatory cytokines due to cell-intrinsic effects of mHTT expression on the NFkB pathway, whereby mHTT interacts with IKK, leading to increased degradation of IkB and subsequent nuclear translocation of RelA. Transcriptional alterations in intracellular immune signaling pathways were also observed. Using a novel method of siRNA delivery to lower HTT expression, this thesis shows a reversal of disease-associated alterations in cellular function - the first time this has been demonstrated in human cells. Glucan-encapsulated siRNA particles (GeRPs) were used to lower HTT levels in human HD monocytes/macrophages, resulting in reversal of HTT-induced elevated cytokine production and transcriptional changes. These findings improve our understanding of the role of innate immunity in neurodegeneration, introduce GeRPs as a tool for studying cellular pathogenesis ex vivo in human cells and raise the prospect of HTT lowering in immune cells as a therapeutic in HD. Evaluating immune function in different mouse models of HD, blood and splenic monocytes replicated the hyper-reactive phenotype seen in HD patients demonstrating that HD mouse models can be of use to understanding HD immune pathology and to test immune modulatory therapies. Furthermore, human HD myeloid cells demonstrated a striking defect in migration towards different chemokines. Looking at the cell’s ability to form filopodia, it became apparent that actin-remodelling is reduced and causes decreased migration. Work performed in collaboration with Novartis revealed that mHTT levels in immune cell subsets differ significantly between disease stages. Monocyte and T cell mHTT levels were significantly associated with disease burden scores and caudate atrophy rates in HD patients. mHTT fragments detected in HD immune cells may explain the progressive increase in mHTT levels. These findings indicate that quantification of mHTT holds significant promise as a non-invasive disease biomarker.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available