Endoplasmic reticulum proteostasis impairment in aging.

Perturbed neuronal proteostasis is a salient feature shared by both aging and protein misfolding disorders. The proteostasis network controls the health of the proteome by integrating pathways involved in protein synthesis, folding, trafficking, secretion, and their degradation. A reduction in the buffering capacity of the proteostasis network during aging may increase the risk to undergo neurodegeneration by enhancing the accumulation of misfolded proteins. As almost one-third of the proteome is synthetized at the endoplasmic reticulum (ER), maintenance of its proper function is fundamental to sustain neuronal function. In fact, ER stress is a common feature of most neurodegenerative diseases. The unfolded protein response (UPR) operates as central player to maintain ER homeostasis or the induction of cell death of chronically damaged cells. Here, we discuss recent evidence placing ER stress as a driver of brain aging, and the emerging impact of neuronal UPR in controlling global proteostasis at the whole organismal level. Finally, we discuss possible therapeutic interventions to improve proteostasis and prevent pathological brain aging.

Targeting the unfolded protein response for disease intervention.

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.