(off)Targeting UPR signaling: the race toward intervening ER proteostasis


The secretory and folding capacity of the cell is constantly challenged by physiological demands and pathological perturbations that disturb the process of protein synthesis and maturation. To adjust the protein folding capacity of the endoplasmic reticulum (ER) according to the need, cells engage a dynamic intracellular signaling pathway known as the unfolded protein response (UPR). Homeostatic activation of the UPR enforces adaptive programs that improve key aspects of the secretory pathway, whereas chronic ER stress results in apoptosis. The generation of genetically modified mice for specific UPR components has uncovered the relevance of the pathway to the physiology of different organs and cell types. Due to the fundamental role of the UPR in controlling protein folding, abnormal levels of ER stress have been associated with a variety of pathologies involving specialized secretory cells, in addition to diseases linked to protein misfolding and aggregation, highlighting cancer, autoimmunity, diabetes, obesity, and neurodegeneration [1]. The UPR has evolved toward the establishment of a complex network of interconnected signaling pathways initiated by the activation of three main type of signal transducers located in the ER known as IRE1α, ATF6, and PERK. Abnormal levels of ER stress have been proposed as a major pathogenic mechanism underlaying in several neurodegenerative diseases, where sustained PERK signaling contributes to neuronal dysfunction and death [2]. Here we discuss recent advances and controversies in the generation of small molecules that inhibit or enhance PERK signaling and their applicability for the treatment of neurodegenerative diseases.

Pérez-Arancibia R, Rivas A, Hetz C

Expert Opinion On Therapeutic Targets (Expert Opin Ther Targets)

febrero 01, 2018

DOI: 10.1080/14728222.2018.1420169

Investigador BNI: Claudio Hetz