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UBC Theses and Dissertations

Microglial dysfunction induced by mutant huntingtin Connolly, Colúm

Abstract

Huntington’s disease (HD) is a devastating, late-onset neurodegenerative disorder that causes profound behavioral abnormalities, language impairment, and alterations in personality in affected patients. HD is an autosomal dominantly inherited disease, caused by a CAG trinucleotide repeat expansion in the huntingtin gene. HD effects up to 1 in 10,000 in populations of European ancestry, but with at least a 10 fold reduced prevalence rate in individuals in Asian or African descent. The critical mechanisms by which the expansion in the huntingtin gene leads to selective neurodegeneration in HD are poorly understood. The purpose of this thesis was to better understand the microglial dysfunction caused by mutant huntingtin and the potential role this microglial dysfunction may play in the pathogenesis of HD. Huntingtin, the protein (HTT) expressed from the huntingtin gene, is ubiquitously expressed in many tissues, with the highest expression levels in brain and testis. Over the last 20 years there have been multiple scientific breakthroughs allowing the development of an array of model systems to investigate HD pathogenesis. Immune dysfunction has recently been implicated in a number of neurodegenerative diseases, including HD. In conclusion, the mechanism of neurodegeneration is not well understood in HD, inflammation could play a pivotal role in the progression of the disease. Inflammation is altered in immune cells containing mutant HTT (mHTT), and although I was unable to provide conclusive evidence that mHTT-induced microglial dysfunction and related neuroinflammation are required for neurodegeneration in an HD mouse model, my work highlights the importance of critically evaluating proposed new disease mechanisms as many will not be directly involved in HD neurodegeneration. My research provides concrete evidence that immune dysfunction occurs in monocyte cells expressing mHTT, however, this cell intrinsic dysfunction does not play a major role in the HD phenotype of the BACHD mouse model.

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Attribution-NoDerivs 2.5 Canada

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