The endoplasmic reticulum stress response in aging and age-related diseases

Abstract

The endoplasmic reticulum(ER) is a multifunctional organelle within which protein folding, lipid biosynthesis, and calcium storage occurs. Perturbations such as energy or nutrient depletion, disturbances in calcium or redox status that disrupt ER homeostasis lead to the misfolding of proteins, ER stress and up-regulation of several signaling pathways coordinately called the unfolded protein response (UPR). The UPR is characterized by the induction of chaperones, degradation of misfolded proteins and attenuation of protein translation. The UPR plays a fundamental role in the maintenance of cellular homeostasis and thus is central to normal physiology. However, sustained unresolved ER stress leads to apoptosis. Aging linked declines in expression and activity of key ER molecular chaperones and folding enzymes compromise proper protein folding and the adaptive response of the UPR. One mechanism to explain age associated declines in cellular functions and age-related diseases is a progressive failure of chaperoning systems. In many of these diseases, proteins or fragments of proteins convert from their normally soluble forms to insoluble fibrils or plaques that accumulate in a variety of organs including the liver, brain or spleen. This group of diseases, which typically occur late in life includes Alzheimer's, Parkinson's, type II diabetes and a host of less well known but often equally serious conditions such as fatal familial insomnia. The UPR is implicated in many of these neurodegenerative and familial protein folding diseases as well as several cancers and a host of inflammatory diseases including diabetes, atherosclerosis, inflammatory bowel disease and arthritis. This review will discuss age-related changes in the ER stress response and the role of the UPR in age-related diseases.

Keywords: BiP/GRP78; UPR; age-related disease; aging; endoplasmic reticulum; stress.

Figure 1

Activation of the unfolded protein response (UPR). Accumulation of misfolded or unfolded proteins in the ER leads to the dissociation of BiP from 3 transducers –PERK, IRE1 and ATF6. PERK homodimerizes and phosphorylates eIF2α to inhibit general protein translation. PERK also regulates several transcription factors including, NRF-2 to up-regulate the anti-oxidant response and ATF4 which can lead to both protective and apoptotic signaling. IRE-1 activation results in the unconventional splicing of XBP-1, which induces the transcription of several molecular chaperones, such as BiP and GRP94 and stimulates protein degradation via ER-associated degradation (ERAD). ATF6 is activated and cleaved and leads to induction of molecular chaperones. The various ER chaperones are part of a protective adaptive response that regulates protein folding and other components of the UPR.

Figure 2

Sustained ER stress leads to pro-apoptotic signaling and cell death. Unresolved ER stress leads to inflammation and cell death pathways involving the PERK and IRE1 branches of the UPR. The IRE1-TRAF2- apoptosis signaling kinase 1 (ASK1) complex upregulates c-jun NH2 terminal kinase (JNK) and caspases and through splicing of XBP1 can activate C/EBP homologous protein (CHOP), a pro-apoptotic transcription factor. PERK signaling, through phosphorylation of eIF2α, can activate ATF4 dependent transcription resulting in activation of nuclear factor-kappaB (NFκB) and increases in CHOP. CHOP and ER specific caspases are thought to directly induce cell death. Several genes that mediate apoptotic function and inflammation are induced by prolonged ER stress.