Abstrato

The effect of imipramine on the response of cells to endoplasmic reticulum stress

Maria Bradnova

 The development and progression of many neurodegenerative diseases has been associated with the process of endoplasmic reticulum stress (ERS). This arises as a result of an accumulation of misfolded proteins in the ER lumen and induces an unfolded protein response (UPR) in cell as an effort to restore cellular homeostasis. This response consists of three pathways, at the beginning of which the sensory proteins on the ER membrane are activated by an increased amount of misfolded proteins.

            Inositol-requiring enzyme 1α (IRE1α) represents one of the UPR pathways. In addition to protein phosphorylation, it acts as endoribonuclease. Upon its activation, non-canonical splicing of X-box-binding protein 1 (XBP1) mRNA occurs and spliced mRNA is then translated to functional transcription factor providing increased expression of gene for E3 ubiquitin ligase synoviolin 1 (SYVN1). SYVN1 plays an important role in mechanism ensuring the degradation of misfolded proteins accumulated in the ER lumen.The aim of this project was to study the effect of the tricyclic antidepressant imipramine (IMI) on UPR of neuroblastoma cells SH-SY5Y in which ERS was induced by tunicamycin or thapsigargin. Imipramine enhanced the effect of ERS in these cells. Its application resulted in increased activation of the IRE1α-pathway, which resulted in an increase in the amount of spliced mRNA for XPB1. However, increased amount of SYVN1 induced by the impact of tunicamycin or thapsigargin application was not reported, which may be the cause of decreased survival of such cells.