Year

2015

Degree Name

Doctor of Philosophy

Department

School of Biological Sciences

Abstract

Huntington’s disease is a progressive neurodegenerative disease caused by a mutation in the huntingtin protein. Although the mutation has been identified, the molecular mechanisms underlying Huntington’s disease pathology are not fully understood. Dysfunction of cholesterol homeostasis has been previously associated with Huntington’s disease, however detailed examination of potential changes has not been undertaken. The aim of this project was to identify cholesterol homeostatic alterations in HD that may be relevant to mechanisms that underlie neurodegeneration, or potentially identify associated molecules to be used as biomarkers of Huntington’s disease. Using a novel triple quadrupole gas chromatography-mass spectrometry method, we have conducted 3 separate studies in R6/1 mice. Firstly, comprehensively characterising the physical phenotype and cholesterol homeostatic alterations during disease progression. These were then used for reference when R6/1 mice were subject to environmental enrichment, and anthocyanin dietary supplementation. Human HD post mortem tissue was also analysed for cholesterol synthetic precursors, metabolites and oxidation products. A progressive dysfunction of cholesterol synthesis was detected in both striatum and cortex of the R6/1 mouse. At later stages in the disease model, the major brain cholesterol metabolite, 24(S)-hydroxycholesterol, was also significantly reduced. Novel age-related changes pertaining to brain cholesterol homeostasis were also detected in these mice. Environmental enrichment of R6/1 mice attenuated the progression of motor dysfunction in male mice. Cholesterol oxidation products, markers of oxidative stress, were also reduced in the cortex of both wild type and R6/1 mice receiving enrichment. Dietary supplementation with anthocyanins also delayed the onset of motor dysfunction in female R6/1 mice. These studies have highlighted a potential sex differences in HD. Human HD post mortem tissue revealed a specific disturbance to cholesterol synthesis in the putamen, as well as elevated cholesterol oxidation products. Consistent with the R6/1 mouse model, 24(S)-hydroxycholesterol levels were significantly reduced in the striatum (caudate and putamen). Enzymes involved in brain cholesterol metabolism (cholesterol 24-hydroxylase) and synthesis (delta(24)-sterol reductase) were also significantly depleted in the putamen. In conclusion we have identified disturbances in cholesterol metabolic and synthetic pathways in both human and R6/1 mouse brain tissue. In addition to being potentially useful biomarkers of disease severity and progression, these alterations may provide further insight into the effects of lipid alterations in HD pathophysiology, and potentially other neurodegenerative disorders.

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