Proteomic profiling and the unfolded protein response in Parkinson's disease




Bauereis, Brian

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Previous studies in Parkinson's disease (PD) models suggest that early events along the path to neurodegeneration involve activation of the ubiquitin-proteasome system (UPS), endoplasmic reticulum-associated degradation (ERAD), and the unfolded protein response (UPR) pathways, in both the sporadic and familial forms of the disease, and thus ER stress may be a common feature. Furthermore, impairments in protein degradation have been linked to oxidative stress as well as pathways associated with ER stress. We hypothesize that either oxidative stress or proteasomal inhibition is the primary initiator in a multi-factorial cascade driving dopaminergic (DA) neurons towards death in the early stages of the disease. We now report results from proteomic analysis of a rotenone-induced oxidative stress model of PD and an epoxomicin-induced proteasomal inhibition model of PD in the human neuroblastoma cell line, SH-SY5Y. Cells were exposed to sub-micromolar concentrations of rotenone and epoxomicin for 48 hours prior to whole cell protein extraction and shotgun proteomic analysis. Evidence for activation of the UPR comes from our observation of up-regulated Binding immunoglobulin Protein (BiP), heat shock proteins, and foldases. We also observed up-regulation of proteins that contribute to the degradation of misfolded or unfolded proteins controlled by the UPS and ERAD pathways. Additionally, we ran our models for an extended amount of time, 72 hours, and performed the same analyses as above. The results suggest that 72 hours may be too long an incubation time to be considered as an early-stage PD model. At the later time point, the increase in misfolded/damaged proteins overcame the cells, resulting in apoptosis. This suggests that the neurons have an endogenous protective power, early on, that could be potentially harnessed for future therapies and/or early reliable diagnostic biomarkers.


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Epoxomicin, Neuroprotection, Parkinson's disease, Proteomics, Rotenone, Unfolded Protein Response



Integrative Biology