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Abstract
Parkinson’s disease (PD) is an idiopathic neurodegenerative disorder affecting 1-2% of the population over 65 years of age. PD is associated with region-specific dopaminergic neuron loss and the formation of Lewy body (LB) inclusions. Alpha-synuclein (-syn) is a major LB component. Colocalisation of lipids with -syn in LBs implies that lipids may have a role in PD. Lipids are abundant in the brain, with cholesterol, sphingolipids (SLs), and glycerophospholipids (GPs) considered the major classes. Cholesterol is metabolised by its conversion to oxysterols. Oxysterols may regulate gene expression through liver X receptors (LXRs). The regulation of -syn expression by the oxysterol/LXR pathway has not been examined. In addition, it is not known if cerebral lipid alterations are associated with human PD. Thus, the two major aims of this thesis were to determine whether LXR activators regulate -syn expression and provide an assessment of the lipid profile in human PD brain. The first aim was addressed by treating cells that endogenously express -syn with LXR ligands including, biologically active 27-hydroxycholesterol, and the second aim was addressed using mass spectrometry (MS), high-performance liquid chromatography (HPLC), and quantitative polymerase chain reaction techniques to generate lipidomic and gene expression profiles of human PD brain tissue.
LXR activation significantly upregulated -syn mRNA and protein expression in neuroblastoma and oligodendrocyte cell lines. LXR induction was confirmed by detection of an increase in the LXR-responsive gene ABCA1. Grey matter from primary visual cortex (VC), amygdala, and anterior cingulate cortex of PD and control donor brains were analysed. Using MS and HPLC methods, changes in SLs, GPs and oxysterols in PD VC were revealed. In addition, many of these lipid changes were correlated with changes in the expression of genes involved in lipid metabolism and an oxidative stress response. The data suggest that altered lipid metabolism and oxidative stress in the VC may be involved in non-motor symptoms, such as visual hallucinations, that are experienced by a majority of PD patients. In summary, these studies identify a role for the oxysterol/LXR pathway in the regulation of -syn expression, and provide the first lipidomics assessment of human PD brain. The latter data also provide the first clues to possible novel treatments and/or diagnostic markers for non-motor complications in PD patients.