| Summary: | Parkinson’s disease (PD) is characterised by loss of dopaminergic neurons within the substantia nigra pars compacta. Mitochondrial dysfunction and oxidative stress are pathological characteristics of PD. It is not fully understood how neurons respond to these stresses, though adaptive responses involving the activity of PD-associated proteins such as Parkin may play a critical role. When these adaptive responses are overcome neurons are lost through apoptotic mechanisms aimed at minimising further tissue damage. AP-1 transcription factors are encoded by immediate early genes (IEGs) such as FOS and JUN. They regulate early cellular responses to stress. Mitogen-associated protein kinases (MAPKs), such as JNK and ERK, regulate AP-1 function. Previous studies have implicated MAPK/AP-1 signalling in the progression of PD. The aim of this thesis was to elucidate whether the AP-1 system was involved in the response to mitochondrial stress in neurons and to dissect the signalling pathways by which this was regulated. SH-SY5Y neuroblastoma cells were used as a model system. CCCP-induced mitochondrial uncoupling induced oxidative stress in this cell line. In response to this AP-1 levels were modulated at both the mRNA and protein levels. SH-SY5Y differentiation or Parkin overexpression altered AP-1 protein response profiles. Treatment with c-Jun siRNA lead to an increase in cell death induced by lower levels of mitochondrial coupling, but a decrease under higher levels of uncoupling. Additionally, a novel link between Parkin and the AP-1 response was observed and investigated. Further work indicated that both JNK and ERK could regulate c-Jun function. Critically, this was dependent on both cell differentiation and the level of stress. Notably, JNK signalling was the primary promoter of apoptosis in response to high levels of mitochondrial stress in differentiated cells. This study suggests that the JNK/c-Jun pathway is differentially regulated by the level of mitochondrial stress, contributing to both adaptive and apoptotic responses and thereby playing a central role in deciding neuronal fate. It further suggests that enhancing adaptive cytoprotective pathways represent a better approach than inhibiting apoptotic pathways when developing therapeutics for the neurodegenerative progression observed in PD.
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