Idiopathic Parkinson??s disease (PD) and the atypical parkinsonian syndromes progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) have substantial overlap in clinical features, with parkinsonian and cerebellar phenotypes identified. Pathologically, reactive glial changes occur in overlapping pathways in these disorders. Recent findings that glia concentrate proteins associated with genetic forms of PD, suggest a more significant role for these cells in the pathogenesis of these disorders. This study is the first to comparatively assess glial abnormalities in PD, PSP and MSA. Cases were clinically and pathologically characterised to establish correlates to prominent glial changes. The three main types of glia (astrocytes, oligodendroglia and microglia) were characterised by morphological features and protein expression (using immunohistochemical techniques) for correlations with disease indices. Tissue features measured included subregional volumes, nigral cell loss, characteristic disease inclusions, and the densities of glia. Using these techniques, the parkin co-regulated gene protein was found to be a novel constituent protein in protoplasmic astrocytes, facilitating the assessment of glial subtypes. The data show that distinct glial abnormalities associate with each parkinsonian syndrome. The most marked differences were observed in the astrocytic reaction in each disorder. In PD, protoplasmic astrocytes accumulated non-fibrillar -synuclein and degenerated over time, relating to a loss of levodopa responsiveness. In PSP, there was a marked protoplasmic astrogliosis (with these reactive glia strongly expressing parkin) that related to PSP-prominent clinical symptoms. In MSA, there was a marked fibrous astrogliosis and a loss of protoplasmic astrocytes in association with early changes in constituent myelin and oligodendroglial proteins. In contrast, similar microglial activation was observed across all disorders, with phagocytes concentrating in the substantia nigra, while non-phagocytic reactive microglia expressed parkin and associated with inclusion formation in each disorder. Overall, the glial reactions were considered to be either contributing to or ameliorating (neuroprotective) the neurodegenerative processes, and the timing of these reactions assessed with respect to indices of disease progression. The novel findings of this thesis show that glial abnormalities are prominent but distinct, and occur early in these parkinsonian syndromes. Suggestions on how these findings may translate into future therapeutic targets are given.
| Identifer | oai:union.ndltd.org:ADTP/258111 |
| Date | January 2008 |
| Creators | Song, Yun Ju Christine, Prince of Wales Medical Research Institute, Faculty of Medicine, UNSW |
| Publisher | Publisher:University of New South Wales. Prince of Wales Medical Research Institute |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | http://unsworks.unsw.edu.au/copyright, http://unsworks.unsw.edu.au/copyright |
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