INVESTIGATION OF HOW ENDOPLASMIC RETICULUM STRESS CAUSES INSULIN RESISTANCE AND NEUROINFLAMMATION

Abstract

Endoplasmic reticulum (ER) stress is caused by the accumulation of mis/unfolded proteins in the ER. ER stress signalling pathways termed the unfolded protein response are employed to alleviate ER stress through increasing the folding capacity and decreasing the folding demand of the ER as well as removing mis/unfolded proteins. However, ER stress signalling pathways induce diverse cellular changes beyond changes to the ER. This study aims to further investigate some of these ER stress-mediated events.

ER stress can cause activation of JNK. Prolonged ER stress-mediated JNK activation is reported to promote apoptosis whilst both acute and long-lasting JNK activation is proposed to cause insulin resistance. To begin with it is reported in this thesis that acute ER stress-induced JNK activation, which is dependent on IRE1α and TRAF2, promotes survival. In contrast to other studies, this thesis provides evidence that acute ER stress-mediated JNK activation does not inhibit insulin signalling during ER stress in several cell lines. However, prolonged ER stress, in four different cell lines, does inhibit insulin signalling in a JNK independent manner. This study argues that ER-stress-induced insulin resistance during prolonged ER stress involves inhibition of trafficking of newly synthesised insulin receptors through the secretory pathway to the plasma membrane.

Finally ER stress can activate inflammatory signalling pathways other than JNK and thus ER stress may promote inflammation. Neuroinflammation and ER stress are reported in Parkinson’s disease (PD) yet a link between them has so far not been investigated. Using a cellular model of PD, it is reported in this thesis that ER stress has the potential to activate neuroinflammation in PD.