whole-musgrove-thesis-2012.pdf (5.03 MB)
Alpha-synuclein in the neurodegenerative mechanisms of Parkinson's disease and dementia with Lewy bodies
thesisposted on 2023-05-26, 02:50 authored by Musgrove, REJ
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.
Rights statementCopyright 2012 the author 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) ˜í¬±-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