The Unfolded Protein Response and Cellular Toxicity: Implications in Neurodegeneration

Abstract

Endoplasmic reticulum (ER) dysfunction has an imperative role in numerous neurological disorders, including, multiple sclerosis, amyotrophic lateral sclerosis, prion diseases and Alzheimer's disease. In disease state, protein misfolding in the endoplasmic reticulum (ER) initiates a stress response, the unfolded protein response (UPR) in neurons due to a rise in proteotoxicity. Although there is an immense effort to explore the pathogenesis of ER dysfunction, unfortunately the exact mechanism is still unclear. Therefore as a preliminary initiative the present study was conducted to investigate one of the aspects of this complex molecular event. The study elucidates the molecular relationship between the unfolded protein response (UPR) during ER stress and aggregation of Amyloid beta that ultimately results in neuronal toxicity leading to neurodegeneration. The experimental animals, Balb/c mice were divided into 4 groups (n=15, each). Dithiothreitol (DTT) was used to induce UPR following ER stress. An optimum dose of DTT (75 mg/kg) was administered after every 24 hours. Histological examination showed a marked formation of amyloid beta plaques in the cortex and hippocampus sections of mice brain along with atrophied neuronal morphology, after 48 to 72 hours of treatment. Differential proteomic analysis was carried out using SDSPAGE followed by ESI-QTOFMS/MS identification. The analysis revealed 10 differentially expressed cortical and hippocampal proteins, involved in various cellular and metabolic pathways. The gene expression analysis performed by Real-Time PCR determined the transcriptional expression of Activating Transcription Factor 6 (ATF6), a UPR regulating protein, and Amyloid Precursor Protein (APP) isoforms (common, 695 770). Furthermore, the immunohistochemical analysis also revealed the nuclear localization of ATF6 during ER stress. In conclusion, the findings of the present work may contributes to the existing pool of knowledge and provide a better understanding of complex molecular association of UPR with AB neurotoxicty that may help in further