Proteomic insights into the protective mechanisms of an in vitro oxidative stress model of early stage Parkinson's disease.
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 oxidative stress is a 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 in the human neuroblastoma cell line, SH-SY5Y. Cells were exposed to sub-micromolar concentrations of rotenone for 48h 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. Activation of the UPR may allow neurons to maintain protein homeostasis in the cytosol and ER despite an increase in reactive oxygen species due to oxidative stress, and activation of the UPS and ERAD may further augment clean-up and quality control in the cell.
Department of Biology, University of Texas at San Antonio, San Antonio, TX 78249, United States.
Brian
B
Bauereis
William E
WE
Haskins
Richard G
RG
Lebaron
Robert
R
Renthal
D000704:Analysis of Variance; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007306:Insecticides / Q000494:pharmacology; D009447:Neuroblastoma / Q000473:pathology / Q000648:ultrastructure; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D020543:Proteome / Q000378:metabolism; D040901:Proteomics; D012402:Rotenone / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D007306:Insecticides; D020543:Proteome; D012402:Rotenone; D053148:Caspase 3