Comparative proteomics reveals the neurotoxicity mechanism of ER stressors tunicamycin and dithiothreitol

Neurotoxicology
Bingyu RenJing Tian

Abstract

Severity or duration of endoplasmic reticulum (ER) stress leads to two different cellular events: cell survival and apoptosis. Drug-induced ER stress or neurotoxicity has been observed as one of the main side effects. However, how ER stress affects cellular signaling cascades leading to neuronal damage is still not well understood. In this study, the toxicological mechanisms of two typical ER stress inducers, tunicamycin (Tm) and dithiothreitol (DTT), were investigated by cell viability, unfolded protein response, apoptosis and proteomic responses in mouse neuro-2a cells. A large portion of differentially expressed proteins (DEPs) that participate in protein synthesis and folding were identified in the Tm treated group, indicating adaptive cellular responses like the unfolded protein response were activated, which was not the case in the DTT treated group. Interestingly, KEGG pathway analysis and validation experiments revealed that proteins involved in proteasomal degradation were down-regulated by both inducers, while proteins involved in ubiquitination were up-regulated by Tm and down-regulated by DTT. A protein responsible for delivering ubiquitinated proteins to the proteasome, the UV excision repair protein RAD23 homolog ...Continue Reading

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