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Alpha-synuclein in the neurodegenerative mechanisms of Parkinson's disease and dementia with Lewy bodies

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Musgrove, REJ (2012) Alpha-synuclein in the neurodegenerative mechanisms of Parkinson's disease and dementia with Lewy bodies. PhD thesis, University of Tasmania.

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Abstract

Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB) are characterised by
Lewy body pathology and the degeneration of midbrain-dopaminergic and cortical
neurons, respectively. The mechanisms underlying the selective degeneration of these
neuronal populations are not known. Gene mutations associated with PD and DLB have
highlighted the role of oxidative stress and mitochondrial dysfunction in the pathogenesis
of these conditions. Substitution mutations in the SNCA gene encoding alpha-synuclein are
the most common cause of familial disease and alpha-synuclein also comprises the
principal component of Lewy bodies. However, the contribution of this protein to
neurodegeneration is uncertain. The intent of this thesis was to further clarify the role of
wild type and mutant alpha-synuclein in the pathogenic mechanisms of PD and DLB.
In vitro models of oxidative stress and mitochondrial dysfunction were applied to primary
neuronal cultures derived from wild type and SNCA null rodent models. Alpha-synuclein
expression was correlated to neuronal health, free radical production, mitochondrial
function and metabolism. Results within this thesis demonstrate that wild-type alphasynuclein
protects both cortical and dopaminergic neurons from oxidative stress. This
response is linked to an increase in its cytoplasmic expression within subgroups of these
neuronal populations. Alpha-synuclein expression did not affect free radical production but
conferred neuroprotection against caspase-dependent apoptosis. This effect was mediated
through the mitogen activated protein kinase (MAPK) signalling pathway. Data within this
thesis also supports a role for alpha-synuclein in facilitating neuronal energy production
through oxidative phosphorylation.
In contrast to wild-type protein, expression of mutant (A35T) alpha-synuclein increased
neuronal susceptibility to oxidative toxicity. However, this mutation was not associated
with induction of a specific apoptotic pathway. Rather mutant (A53T) alpha-synuclein was
linked to sensitisation of neurons through a toxic gain of function which was independent
of mitochondrial free-radical production or calcium buffering.
In summary, the studies within this thesis have clarified the contribution of alpha-synuclein
to normal neuronal function and the mechanisms of PD and DLB. The results have
highlighted complexities surrounding the contentious role of alpha-synuclein in both
neuroprotection and toxicity. Based on these findings, a sound hypothesis for the role of
this protein in the pathogenesis of PD and DLB has been proposed. Significantly, this twohit
hypothesis validates past studies, which have detailed a role of alpha-synuclein in both
neuroprotection through chaperone activity, and in neurotoxicity through a toxic gain of
function mechanism. This thesis will provide a basis and direction for further
investigations into the relationship between intracellular alpha-synuclein levels, and the
selective nature of neurodegeneration in PD and DLB.

Item Type: Thesis (PhD)
Keywords: alpha-synuclein, Parkinson's disease, demetia with Lewybodies, neurodegeneration
Copyright Information:

Copyright 2012 the author

Additional Information:

Chapter 3 appears to be the equivalent of the post-print version of an article published as: Musgrove RE, King AE, Dickson TC (2011) Neuroprotective upregulation of endogenous alpha-synuclein precedes ubiquitination in cultured dopaminergic neurons, Neurotoxicity research, 19(4), 592-602. The final publication is available at Springer via http://dx.doi.org/10.1007/s12640-010-9207-x

Chapter 4 appears to be the equivalent of the post-print version of an article published as: Musgrove RE, King AE, Dickson TC (2013) α-synuclein protects neurons from apoptosis downstream from free radical production through modulation of the MAPK signaling pathway, Neurotoxicity research, 23(4), 358-369. The final publication is available at Springer via http://dx.doi.org/10.1007/s12640-012-9352-5

Date Deposited: 13 Feb 2013 01:17
Last Modified: 12 Sep 2016 02:37
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