Parkinson???s disease (PD) is a progressive neurodegenerative disease characterised pathologically by the selective death of the dopaminergic neurons of the substantia nigra and the appearance of abnormal inclusions in some surviving neurons. A body of evidence from epidemiological, in vitro and in vivo studies suggest that isoprenoids, a lipid family which includes cholesterol, dolichol and ubiquinone, may play a role in PD, although to date the data has been conflicting with little consensus regarding the type or direction of change in isoprenoids in PD. The current study investigated isoprenoids in PD by quantifying a range of isoprenoids in blood sera, brain homogenates and olfactory mucosa derived from PD patients and controls. Further, isoprenoid synthesis pathways were investigated by comparing the activitites and amount of the rate-limiting enzyme for isoprenoid synthesis, HMG CoA reductase, in olfactory mucosal cultures from individuals with sporadic PD and leucine-rich repeat kinase 2 (LRRK2)-PD with those from healthy individuals. Serum levels of total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides and dolichol were unchanged in patients with PD compared with controls. Similarly, total tissue cholesterol was unchanged in degenerating and non-degenerating regions of the PD brain, but tissue dolichol was significantly decreased in the substantia nigra in the PD brain, possibly reflecting a change in the neuron/glia ratio in this brain region. In olfactory mucosa, a significant decrease in cellular cholesterol content was identified in patients with LRRK2-PD compared with patients with sporadic PD or controls. The reduction in cholesterol was similar in two different LRRK2 mutations but was not associated with a change in either the amount or activity of HMG CoA reductase. This study suggests that decreased cholesterol is associated with LRRK2-PD but not with sporadic PD. As cholesterol levels in cells with different LRRK2 mutations were reduced to a similar extent, it is suggested that mutations in this gene result in a loss-of-function of LRRK2 protein. Further it suggests a role for LRRK2 in cholesterol homeostasis independent of HMG-CoA reductase-associated pathways. Recent data has suggested a functional role of LRRK2 in autophagy, a mechanism which may explain the reduction in cholesterol observed in LRRK2-PD.
| Identifer | oai:union.ndltd.org:ADTP/279633 |
| Date | January 2009 |
| Creators | Ng, Khuen Yen, Prince of Wales Medical Research Institute, Faculty of Medicine, UNSW |
| Publisher | Awarded by:University of New South Wales. Prince of Wales Medical Research Institute |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | Copyright Ng Khuen Yen., http://unsworks.unsw.edu.au/copyright |
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