Chonnam Med J.  2019 Jan;55(1):8-19. 10.4068/cmj.2019.55.1.8.

Endoplasmic Reticulum Stress: Implications for Neuropsychiatric Disorders

• Muneer A
• Shamsher Khan RM

• KMID: 2432250
• DOI: http://doi.org/10.4068/cmj.2019.55.1.8

Abstract

The Endoplasmic reticulum (ER), an indispensable sub-cellular component of the eukaryotic cell carries out essential functions, is critical to the survival of the organism. The chaperone proteins and the folding enzymes which are multi-domain ER effectors carry out 3-dimensional conformation of nascent polypeptides and check misfolded protein aggregation, easing the exit of functional proteins from the ER. Diverse conditions, for instance redox imbalance, alterations in ionic calcium levels, and inflammatory signaling can perturb the functioning of the ER, leading to a build-up of unfolded or misfolded proteins in the lumen. This results in ER stress, and aiming to reinstate protein homeostasis, a well conserved reaction called the unfolded protein response (UPR) is elicited. Equally, in protracted cellular stress or inadequate compensatory reaction, UPR pathway leads to cell loss. Dysfunctional ER mechanisms are responsible for neuronal degeneration in numerous human diseases, for instance Alzheimer's, Parkinson's and Huntington's diseases. In addition, mounting proof indicates that ER stress is incriminated in psychiatric diseases like major depressive disorder, bipolar disorder, and schizophrenia. Accumulating evidence suggests that pharmacological agents regulating the working of ER may have a role in diminishing advancing neuronal dysfunction in neuropsychiatric disorders. Here, new findings are examined which link the foremost mechanisms connecting ER stress and cell homeostasis. Furthermore, a supposed new pathogenic model of major neuropsychiatry disorders is provided, with ER stress proposed as the pivotal step in disease development.

Keyword

Endoplasmic Reticulum; Unfolded Protein Response; Proteostasis Deficiencies; Apoptosis; Biological Psychiatry

MeSH Terms

Apoptosis
Biological Psychiatry
Bipolar Disorder
Calcium
Depressive Disorder, Major
Endoplasmic Reticulum Stress*
Endoplasmic Reticulum*
Eukaryotic Cells
Homeostasis
Humans
Neurons
Neuropsychiatry
Oxidation-Reduction
Peptides
Proteostasis Deficiencies
Schizophrenia
Unfolded Protein Response
Calcium
Peptides

Figure

• 

  FIG. 1 Cellular adaptive response to endoplasmic reticulum (ER) stress. Increase in unfolded proteins can be instigated by physiological as well as disease factors. The latter may include defects in protein folding, calcium changes, redox imbalance and inflammatory signaling, resulting in the unfolded protein response (UPR). The cellular reaction to UPR involves other organelles, such as the mitochondria, and either leads to re-establishing cell homeostasis or relegating them to death. The cascades activated by UPR result in such adaptive reactions like ER associated biogenesis, ER-associated degradation (ERAD) via the ubiquitin-proteasome system and autophagy. When these regulating mechanisms are overwhelmed, stress sensors responsible for UPR commit cells to apoptosis.

• 

  FIG. 2 Canonical mediators of the unfolded protein response (UPR). A third of all human proteins are folded into 3-dimensional conformations in the endoplasmic reticulum (ER) before they can perform their roles in cells. If a cell is required to make a large number of proteins, or in disease states unfolded proteins may accumulate in the ER. The organism responds to this stress by triggering the UPR which is mediated by three ER stress sensors-the inositol-requiring enzyme 1 (IRE1), the activating transcription factor 6 (ATF6) and protein kinase RNA-like ER kinase (PERK). These stimulate a complex transcriptional cascade with ensuing adaptive responses which restore the folding capabilities of the ER. However, if the ER stress exceeds the capacity of this built-in quality control, cell death is incited through the up-regulation of the pro-apoptotic arm of the UPR pathway to protect the organism from the toxicity of misfolded proteins.

• 

  FIG. 3 Molecular mechanisms of endoplasmic reticulum stress response. Build-up of unfolded proteins in the ER lumen signals the unfolded protein response. The activated stress sensors —protein kinase RNA-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6 (ATF6) - stimulate diverse cascades seeking to reinstate cell homeostasis or assign it to death. Here, the molecular events that occur in this process are explained in a simplified manner. In brief, IRE1 and ATF6 increase levels of XBP1 which is a diverse transcription factor and leads to increased expression of chaperones and other proteins involved in protein folding in ER. PERK, by virtue of phosphorylating elongation factor 2α (elf2α) puts a hold on translation, enabling ER to recover its protein folding capabilities. However, the expression of ATF4 is also increased which causes activation of CHOP and programmed cell death. The latter is also facilitated by c-Jun N-terminal kinase (JNK), a transcription factor stimulated by activated ATF6. CHOP: CCAAT/enhancer-binding protein homologous protein, ER: endoplasmic reticulum, ERAD: endoplasmic reticulum-associated protein degradation.

• 

  FIG. 4 A cellular pathogenic model of disease development in major psychiatric disorders. Major psychiatric disorders including mood disorders, psychotic disorders and neurodegenerative disorders are characterized by increased endoplasmic reticulum (ER) stress. ER chaperones act as first line of defense against unfolded or misfolded proteins, but accumulation of non-natively conformed polypeptides in the ER lumen activates other compensatory mechanisms. ER and mitochondria work in close unison through the mitochondria-associated ER membranes, stimulating the mitochondrial unfolded protein response (UPR mt). However, in cellular stress increased generation of reactive oxygen species (ROS) and build up of intracellular calcium ions further exacerbates ER/mt stress. During proteostasis, unfolded/misfolded proteins are degraded via the ubiquitin-proteasome system but when the latter gets saturated, toxic oligomers or larger aggregates accumulate, which can then be got rid of through lysosomal autophagic mechanisms. Since lysosomal dysfunction is present in many neuropsychiatric diseases, accumulated protein aggregates acting as danger associated molecular patterns cause activation of the inflammasome leading to inflammatory-immune signaling and ultimately increased apoptosis of neurons. This cascade is responsible for increased damage to neurons and its further elucidation can result in the development of novel therapeutic agents for otherwise recalcitrant neuropsychiatric diseases.

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