Cell proliferation and metal accumulation in the subventricular zone and olfactory bulb in Parkinson’s disease

Parkinson’s disease (PD) is characterised by four main motor symptoms: resting tremor, rigidity, bradykinesia, and postural instability. However, over 95% of PD patients also report a decline or total loss in the ability to smell, which often occurs years before any motor symptoms develop. Possible causes for this olfactory dysfunction include a decrease in subventricular zone neurogenesis, caused by dopaminergic denervation of this region, or an accumulation of metals from the environment. In this thesis, immunohistochemistry was used to investigate proliferation levels and dopamine receptor abundance in the subventricular zone of normal and PD human brains. There was no change in the number of cells expressing proliferating cell nuclear antigen (PCNA) or the D1 or D2 dopamine receptor subtypes in PD, suggesting that olfactory dysfunction in PD is not caused by a decrease in subventricular zone cell proliferation. However, these studies also demonstrated that in PD brains that were treated with chronic deep brain stimulation (DBS) there were higher levels of proliferation in both the subventricular zone and third ventricle regions. This upregulation in endogenous neural proliferation may be important for ongoing neural plasticity, and may contribute to the efficacy of this therapy. In PD there is also an alteration in metal concentrations in the brain. In the second half of this thesis, laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) was employed to compare localised metal concentrations in normal and PD brains for the first time, and a data analysis pipeline was developed to display the resulting data. This technique was then used to investigate iron, copper, zinc, and manganese in the subventricular zone and olfactory bulb, both of which may be particularly vulnerable to metal accumulation. In the PD subventricular zone, zinc was significantly higher compared to the normal population, which may relate to the importance of zinc for cell proliferation. For olfactory bulb studies, inductively coupled plasma mass spectrometry (ICP-MS) of homogenised tissue was also used to investigate total quantities of a range of metals. In this region, sodium and iron were significantly higher in PD, and may be implicated in olfactory dysfunction in this disease. Overall, the findings from this thesis demonstrate a possible role for metal dyshomeostasis in the olfactory dysfunction in PD, and identify new avenues of research for the treatment of PD.

Name thesis:degree_name

PhD

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Biomedical Science

Grantor dc:publisher

ResearchSpace@Auckland

Year dc:date.issued

2016

Author dc:creator

• Gardner, Bronwen

Advisor dc:contributor.advisor

• Curtis, M

Statement dc:rights

• Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher.

Licence dc:rights.uri

• https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm

Handle dc:identifier.uri

https://hdl.handle.net/2292/29505

OAI identifier oai:identifier

oai:researchspace.auckland.ac.nz:2292/29505