Targeting the unfolded protein response for disease intervention

Abstract

Introduction: The accumulation of misfolded proteins in the endoplasmic reticulum (ER) generates a stress condition that engages the unfolded protein response (UPR). The UPR is an adaptive reaction that aims to reestablish ER proteostasis by recovering the folding capacity of the cell. However, chronic ER stress results in apoptosis.

Areas covered: This review focuses on discussing the emerging role of the UPR as a driver of several human pathologies including diabetes, neurodegenerative diseases and cancer. The involvement of specific UPR signaling components on different diseases is highlighted based on preclinical models and pharmacological and genetic manipulation of the pathway.

Expert opinion: Therapeutic strategies directed to regulate the activity of different UPR signaling arms may reduce stress levels with a therapeutic gain. Recent drug discovery efforts have identified small molecules that target specific UPR components, providing protection on various disease models. However, important side effects are predicted in the chronic administration due to the fundamental role of the UPR in highly secretory organs such as liver and pancreas. To overcome these problems, we propose the use of combinatorial treatments of selected drugs with natural compounds that are known to modulate the ER proteostasis network.

Keywords:

• endoplasmic reticulum stress signaling.
• pharmacological modulator
• protein misfolding disorders
• unfolded protein response

Acknowledgments

We apologize to all colleagues whose work could not be cited owing to space limitations.

Declaration of interests

This work was funded by Biomedical Neurosciences Institute, Fundacion COPEC-UC, FONDECYT 1140549, Millennium Institute No. P09-015-F, Ring Initiative ACT1109, FONDEF grant No. D11I1007, CONICYT grant USA 2013-0003, The Michael J. Fox Foundation for Parkinson Research, Frick Foundation (CH), and FONDECYT 1150608 (RV). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Notes

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