Endoplasmic Reticulum Stress-Associated Neuronal Death and Innate Immune Response in Neurological Diseases

Abstract

Neuronal death and inflammatory response are two common pathological hallmarks of acute central nervous system injury and chronic degenerative disorders, both of which are closely related to cognitive and motor dysfunction associated with various neurological diseases. Neurological diseases are highly heterogeneous; however, they share a common pathogenesis, that is, the aberrant accumulation of misfolded/unfolded proteins within the endoplasmic reticulum (ER). Fortunately, the cell has intrinsic quality control mechanisms to maintain the proteostasis network, such as chaperone-mediated folding and ER-associated degradation. However, when these control mechanisms fail, misfolded/unfolded proteins accumulate in the ER lumen and contribute to ER stress. ER stress has been implicated in nearly all neurological diseases. ER stress initiates the unfolded protein response to restore proteostasis, and if the damage is irreversible, it elicits intracellular cascades of death and inflammation. With the growing appreciation of a functional association between ER stress and neurological diseases and with the improved understanding of the multiple underlying molecular mechanisms, pharmacological and genetic targeting of ER stress are beginning to emerge as therapeutic approaches for neurological diseases.

Keywords: endoplasmic reticulum stress; inflammatory response; neurological diseases; neuronal death; proteostasis; unfolded protein response.

Figure 1

Sensing and responding to endoplasmic reticulum stress: canonical roles of unfolded protein response. In response to an increasingly accumulation of misfolded proteins in endoplasmic reticulum (ER) lumen, three sensors that located in ER membrane — inositol-requiring enzyme 1α (IRE1α), protein kinase RNA-like ER kinase (PERK) and activating transcription factor 6 (ATF6) — provoke unfolded protein response (UPR). Under homeostatic conditions, ER-resident protein chaperone glucose regulated protein 78 (GRP78) interacts with these ER stress sensors to restrain their activation. However, the excessive accumulation of misfolded proteins recruit GRP78 away from all three ER stress sensors, leading to activation of downstream signal transduction pathways. Upon ER stress, PERK undergoes its dimerization and autophosphorylation to phosphorylate eukaryotic translation initiator 2α (eIF2α), which then selectively increases translation of activating transcription factor 4 (ATF4). ATF4 modulates the expression of genes involved in redox control, amino acid metabolism, autophagy, apoptosis, and protein synthesis and folding. Additionally, Phosphorylated eIF2α (p-eIF2α) prevents ribosome assembly, which results in a translational block. Once ER stress is resolved, p-eIF2α is dephosphorylated by the GADD34-protein phosphatase 1 (PP10) complex to restore protein translation. In response to ER stress, IRE1α oligomerizes and promote autophosphorylation, eliciting RNase activity to splice the mRNA of x-box-binding protein 1 (XBP1). Spliced XBP1(XBP1s) mRNA codes for the functionally active proteins of XBP1s, which translocated into nuclear and subsequently induces the transcription of various genes that are involved in protein folding, lipid metabolism and ER-assisted protein degradation (ERAD). In addition, the RNase activity of IRE1α can also degrades a subset of mRNAs in a process termed regulated IRE1α-dependent decay (RIDD). By interacting with adaptor protein TNF receptor-associated factor 2 (TRAF2), IRE1α can also activate c-Jun N-terminal kinase (JNK) and nuclear factor κB (NF-κB) pathways, thereby modulating inflammation and apoptosis. Upon ER stress, ATF6 is transported to Golgi, where it is cleaved by Site-1 protease (S1P) and Site-2 protease (S2P), releasing its active cytosolic fragment (ATF6f) that functions as a transcription factor. ATF6f induces genes required for ERAD and modulates the XBP1 mRNA levels and ER chaperone expression.

Figure 2

Inflammatory response induced by the unfolded protein response. Upon ER stress, PERK undergoes its dimerization and autophosphorylation to phosphorylate eukaryotic translation initiator 2α (eIF2α) and Janus kinase 1(JAK1), which respectively promote activating transcription factor 4 (ATF4) expression and signal transducer and activator of transcription 3 (STAT3) phosphorylation, thereby leading to inflammatory gene expression. In addition, translation attenuation by PERK-dependent phosphorylation of eIF2α results in decreased translation of both IκB and nuclear factor κB (NF-κB) but elevation of the proportion of NF-κB to IκB, owing to the shorter half-life of IκB, thereby promoting NF-κB-mediated inflammatory response. In response to ER stress, activation of inositol-requiring enzyme 1α (IRE1α) increase the expression of functionally active proteins of XBP1s, leading to inflammatory gene expression. During ER stress, interaction of IRE1α and TRAF2 can promote NF-κB-mediated inflammatory response by triggering IκB kinase (IKK)/κB pathway and nucleotide-binding oligomerization domain 1 and 2 (NOD1/2)/receptor-interacting serine/threonine-protein kinase 2 (RIPK2) pathways. In addition, both IRE1α-mediated IRE1α-dependent decay (RIDD)/retinoic-acid inducible gene 1 (RIG-1) pathway and IRE1α-induced expression of spliced x-box-binding protein 1 (XBP1s) are responsible for activating NF-κB. In addition to the activation of NF-κB, IRE1α-TRAF2 complex can also recruit apoptosis signal-regulating kinase 1 (ASK1) and subsequently activate JNK, thereby resulting in expression of pro-inflammatory genes by stimulating the bZIP transcription factor activator protein 1(AP-1). Upon ER stress, ATF6 is transported to Golgi, where it is cleaved by Site-1 protease (S1P) and Site-2 protease (S2P), releasing its active cytosolic fragment (ATF6f). ATF6f as a transcription factor, directly participate in regulating inflammatory response. Besides, ATF6f can also activate NF-κB by inducing the phosphorylation of the AKT.

Figure 3

Proposed mechanism by which endoplasmic reticulum stress signaling impacts the overall central nervous system envirment. Various neurological diseases share a common pathogenesis, that is aberrant accumulation of misfolded proteins within the endoplasmic reticulum (ER). Pathologically, accumulation of misfolded proteins in ER subsequently triggers ER stress and concomitant unfolded protein response (UPR) in microglia, astrocytes, and neurons in various neurological diseases. ER stress occurred in neurons can trigger UPR, resulting in a series of neuronal damage including cell death (apoptosis, necroptosis, pyroptosis, and autophagy), spine elimination, demyelination, synaptic loss, and synaptic plasticity impairment. In addition, UPR-activated microglia promote the polarization of microglia from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype. Similarly, UPR-activated astrocytes exhibit an increase of inflammatory response but a decrease of neurotrophic support. Importantly, both microglia-mediated and astrocyte-mediated inflammatory responses can “transmit” ER stress to neurons, thereby aggravating neuronal damage.