Impaired capacity to restore proteostasis in the aged brain after ischemia: Implications for translational brain ischemia research

Abstract

Brain ischemia induced by cardiac arrest or ischemic stroke is a severe form of metabolic stress that substantially disrupts cellular homeostasis, especially protein homeostasis (proteostasis). As proteostasis is fundamental for cellular and organismal health, cells have developed a complex network to restore proteostasis impaired by stress. Many components of this network - including ubiquitination, small ubiquitin-like modifier (SUMO) conjugation, autophagy, and the unfolded protein response (UPR) - are activated in the post-ischemic brain, and play a crucial role in cell survival and recovery of neurologic function. Importantly, recent studies have shown that ischemia-induced activation of these proteostasis-related pathways in the aged brain is impaired, indicating an aging-related decline in the self-healing capacity of the brain. This impaired capacity is a significant factor for consideration in the field of brain ischemia because the vast majority of cardiac arrest and stroke patients are elderly. In this review, we focus on the effects of aging on these critical proteostasis-related pathways in the brain, and discuss their implications in translational brain ischemia research.

Keywords: Aging; Brain ischemia; Cardiac arrest; Neuroprotection; Protein homeostasis; Stroke.

Figure 1.. The unfolded protein response (UPR).

Brain ischemia causes endoplasmic reticulum (ER) stress that activates UPR. The UPR pathway has 3 response branches controlled by 3 ER stress sensors – protein kinase R-like ER kinase (PERK), activating transcription factor-6 (ATF6), and inositol-requiring enzyme-1 (IRE1). Dissociation of GRP78/BiP (a major ER chaperone) from the ER stress sensors provides a mechanism to activate the UPR branches. Activation of the PERK branch results in phosphorylation of eukaryotic initiation factor 2?? (eIF2α), which inhibits global protein translation. Activation of the ATF6 and IRE1 branches generates 2 transcriptional factors – short form ATF6 (sATF6) and spliced Xbp1 (XBP1s). These transcriptional factors regulate expression of genes that are involved in the processes of protein folding, ER-associated degradation (ERAD), hexosamine biosynthetic pathway (HBP)/O-linked β-N-acetylglucosamine (O-GlcNAc), and autophagy.