Review Article

www.cmj.ac.kr

Endoplasmic Reticulum Stress: Implications for Neuropsychiatric

Disorders
Ather Muneer * and Rana Mozammil Shamsher Khan
1, 2

1
Islamic International Medical College, Riphah International University, Rawalpindi, 2Government Khawaja Safdar Medical College,
Sialkot, Pakistan

The Endoplasmic reticulum (ER), an indispensable sub-cellular component of the eu- Article History:
karyotic cell carries out essential functions, is critical to the survival of the organism. Received September 4, 2018
Revised October 11, 2018
The chaperone proteins and the folding enzymes which are multi-domain ER effectors
Accepted November 9, 2018
carry out 3-dimensional conformation of nascent polypeptides and check misfolded pro-
tein aggregation, easing the exit of functional proteins from the ER. Diverse conditions,
for instance redox imbalance, alterations in ionic calcium levels, and inflammatory sig-
naling can perturb the functioning of the ER, leading to a build-up of unfolded or mis-
folded 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 neu-
ronal degeneration in numerous human diseases, for instance Alzheimer’s, Parkinson’s
and Huntington’s diseases. In addition, mounting proof indicates that ER stress is in-
criminated in psychiatric diseases like major depressive disorder, bipolar disorder, and
schizophrenia. Accumulating evidence suggests that pharmacological agents regulat-
ing the working of ER may have a role in diminishing advancing neuronal dysfunction
in neuropsychiatric disorders. Here, new findings are examined which link the fore-
most mechanisms connecting ER stress and cell homeostasis. Furthermore, a supposed
new pathogenic model of major neuropsychiatry disorders is provided, with ER stress Corresponding Author:
Ather Muneer
proposed as the pivotal step in disease development.
Islamic International Medical College,
Riphah International University, 274
Key Words: Endoplasmic Reticulum; Unfolded Protein Response;
Peshawar Road, Rawalpindi 2244,
Proteostasis Deficiencies; Apoptosis; Biological Psychiatry Pakistan
Tel: +92-51-548-1828
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial
License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, Fax: +92-51-512-5170
distribution, and reproduction in any medium, provided the original work is properly cited. E-mail: muneerather2@gmail.com

HIGHLIGHTS ous human diseases, including neuropsychiatric ailments.

• The finding that several chemicals including some new-
• Unfolded protein response (UPR) is the mechanism ly discovered small non-toxic molecular compounds regu-
whereby eukaryotic cells ensure three dimensional con- late ER - related processes has the promise of uncovering
formation of secreted proteins which is essential for fresh avenues in the treatment of many recalcitrant neuro-
functioning. psychiatric disorders.
• Sensor molecules located in the endoplasmic reticulum
acting as mediators, maintain proteostasis under physio- INTRODUCTION
logical and stressful conditions.
• In disease states when these inherent mechanisms are Under both physiological conditions and cellular stress
overwhelmed, misfolded proteins accumulate and the pro- the unfolded protein response (UPR) embodies a conserved
apoptotic branch of the UPR is activated. reaction ensuring protein quality control and cell survival.1
• Endoplasmic reticulum stress is implicated in numer- At the sub-cellular level the endoplasmic reticulum (ER)

https://doi.org/10.4068/cmj.2019.55.1.8
Ⓒ Chonnam Medical Journal, 2019 8 Chonnam Med J 2019;55:8-19
 Ather Muneer and Rana Mozammil Shamsher Khan

wields the UPR, as here, new proteins are synthesized, nas- leads to the activation of the pro-apoptotic branch of the
cent polypeptides are given 3-D conformation, and post- UPR and cell death (Fig. 1).
translational modifications take place. To perform its var- ER related stress mechanisms are incriminated in nu-
ied functions, the ER undertakes crucial interactions with merous human diseases including neuropsychiatric dis-
other organelles, particularly mitochondria to regulate orders, diabetes mellitus, cancer, cardiovascular, kidney,
proteostasis and relegate misshapen proteins to deg- and pulmonary diseases. With respect to cellular resilience
radation. In this regard, the ER and mitochondria lie in pathways, UPR signaling takes part in growth and devel-
close apposition and share a significant portion of their opment, and is also involved in proper brain functioning
membranes called ‘mitochondria-associated membranes’ through long-term potentiation and neuronal plasticity
or (MAM). In the case of UPR, mutant proteins are de- processes.5
graded via catabolic pathways characterized by the ubiq-
uitin proteasome system and autophagic lysosomes.2 As an ER STRESS SENSORS AND THE UPR-AN
integral function, the ER wields the unfolded protein re- OVERVIEW
sponse to protect the cell from toxicity of accumulated un-
folded/misfolded proteins, whereas mitochondria also The mediators of UPR are three bona fide effectors name-
have their own protein quality control system, the UPR ly, inositol-requiring enzyme 1 (IRE1), activating tran-
(mt).3 scription factor 6 (ATF6), and protein kinase RNA-like ER
ER buildup of unfolded proteins may be caused by such kinase (PERK) that regulate a multifaceted cascading
diverse factors as genetic defects in protein folding, post- pathway.6 Fig. 2 depicts in a simplified manner the canon-
translational modifications, intracellular calcium alter- ical ER catalysts responsible for executing the intrinsic
ations, redox imbalance, and inflammatory signaling. The protein quality control system (Fig. 2).
UPR either results in reinstating cell homeostasis or con- Glucose related protein (GRP) 78, alternatively called
signing them to apoptosis; the adaptive processes are rep-
resented by ER associated biogenesis, the ubiquitin-pro-
teasome system and autophagy.4 Fig. 1 schematically
shows these compensatory mechanisms, whose failure

FIG. 2. Canonical mediators of the unfolded protein response

(UPR). A third of all human proteins are folded into 3-dimensional
FIG. 1. Cellular adaptive response to endoplasmic reticulum (ER) conformations in the endoplasmic reticulum (ER) before they can
stress. Increase in unfolded proteins can be instigated by physio- perform their roles in cells. If a cell is required to make a large num-
logical as well as disease factors. The latter may include defects ber of proteins, or in disease states unfolded proteins may accumu-
in protein folding, calcium changes, redox imbalance and in- late in the ER. The organism responds to this stress by triggering
flammatory signaling, resulting in the unfolded protein response the UPR which is mediated by three ER stress sensors-the in-
(UPR). The cellular reaction to UPR involves other organelles, ositol-requiring enzyme 1 (IRE1), the activating transcription fac-
such as the mitochondria, and either leads to re-establishing cell tor 6 (ATF6) and protein kinase RNA-like ER kinase (PERK).
homeostasis or relegating them to death. The cascades activated These stimulate a complex transcriptional cascade with ensuing
by UPR result in such adaptive reactions like ER associated bio- adaptive responses which restore the folding capabilities of the
genesis, ER-associated degradation (ERAD) via the ubiq- ER. However, if the ER stress exceeds the capacity of this built-in
uitin-proteasome system and autophagy. When these regulating quality control, cell death is incited through the up-regulation of
mechanisms are overwhelmed, stress sensors responsible for the pro-apoptotic arm of the UPR pathway to protect the organism
UPR commit cells to apoptosis. from the toxicity of misfolded proteins.

9
Endoplasmic Reticulum Stress

BiP is an ER chaperone, closely associated with the launch-

ing of UPR, and is among the best studied in this family of
proteins.7 When the misshapen protein load increases in
ER lumen, GRP78 dissociates from trans-membrane sen-
sors kicking off the UPR. In this regard, ATF6 leads to the
transcription of main ER chaperones and X-box binding
protein-1 (XBP1). The endonuclease action of IRE1 cata-
lyzes the splicing of XBP1 mRNA, causing the formation
of an active transcription factor that regulates the ex-
pression of genes involved in the execution of UPR. The
working together of ATF6 and IRE1-XBP1 facilitates the
expression of ER chaperones, promotes the accurate con-
figuration of the secreted proteins, prevents their accumu-
lation, and enhances the continued existence of the cells.8
Conversely, when this compensatory mechanism is over-
whelmed, the pro-apoptotic branch of the UPR is triggered
by activated PERK; initially it dampens overall protein
translation by phosphorylating the eukaryotic initiation
factor 2 (eIF2) and decreasing the total amount of se-
creted proteins in the ER lumen. However, phosphorylated
PERK also promotes the translation of some UPR-related
genes including ATF4, inducing the activation of C/EBP
homologous protein (CHOP). The later acts as a tran-
scription factor that provokes cell death by directly inhibit-
ing the expression of anti-apoptotic factor, Bcl-2.9 Fig. 3 FIG. 3. Molecular mechanisms of endoplasmic reticulum stress
provides an illustrated version of the main molecular response. Build-up of unfolded proteins in the ER lumen signals
events of the UPR in eukaryotic cells (Fig. 3). the unfolded protein response. The activated stress sensors —pro-
tein kinase RNA-like ER kinase (PERK), inositol-requiring en-
zyme 1 (IRE1) and activating transcription factor 6 (ATF6) - stim-
CANONICAL EFFECTORS OF UPR
ulate diverse cascades seeking to reinstate cell homeostasis or as-
sign it to death. Here, the molecular events that occur in this proc-
Membrane spanning catalysts in the ER act as sensing ess are explained in a simplified manner. In brief, IRE1 and ATF6
molecules and identify such perturbations as build-up of increase levels of XBP1 which is a diverse transcription factor and
mutant proteins, variations in the levels of reactive oxygen leads to increased expression of chaperones and other proteins in-
species (ROS) and ionic calcium fluxes. IRE1, PERK and volved in protein folding in ER. PERK, by virtue of phosphorylat-
ATF6, the three main mediators guaranteeing proteo- ing elongation factor 2 (elf2) puts a hold on translation, en-
stasis, i.e. proper secretion, assembly and incorporation of abling ER to recover its protein folding capabilities. However, the
translated proteins, ensure cell homeostasis. These are expression of ATF4 is also increased which causes activation of
discussed in further detail below. CHOP and programmed cell death. The latter is also facilitated
by c-Jun N-terminal kinase (JNK), a transcription factor stimu-
1. Inositol-requiring enzyme 1 alpha (IRE1) lated by activated ATF6. CHOP: CCAAT/enhancer-binding pro-
tein homologous protein, ER: endoplasmic reticulum, ERAD: en-
IRE1 has a reactive kinase region projecting in the cyto-
doplasmic reticulum-associated protein degradation.
sol and a luminal endoribonuclease domain; once activated
by oligomerization and phosphorylation it plays a crucial
role in protein quality control. Indeed, the endoribonu- way of functioning of IRE1 is at disagreement with earlier
clease cuts out a 26 bp intron from the pre-mRNA of XBP-1 conceptualizations which assumed that the binding of BiP
resulting in the formation of a dynamic transcription by unfolded proteins was critical in triggering IRE1
factor. The latter has such major effects as up-regulation signaling. Nevertheless, it is probable that BiP has a role
of ER chaperone genes and the modulation of ERAD.10 in ensuring finer control of UPR so that its increased ex-
Thus, XBP-1 enhances the protein folding capacity of the pression reduces ER stress and enhances cell survival.
ER and accelerates degradation of misfolded proteins, en-
suring cell survival. New light is shed on the crystalline 2. Protein kinase RNA-like endoplasmic reticulum kinase
composition of yeast IRE1 as nascent peptides interact (PERK)
with its luminal projection and subsequently IRE1 oligom- The most important substrate of this enzyme is the eu-
ers are produced via self-association, which are observable karyotic translation initiation factor-2 (eIF2) whose
as large structures in the ER.11 Demonstrated thus far in phosphorylation causes an overall decrease in protein pro-
fungi, the eukaryotic IRE1 shows a somewhat similar con- duction and results in a reduction in the quantity of mis-
figuration signifying a comparable type of control.12 This folded polypeptides. Nevertheless, the hold on translation

10
 Ather Muneer and Rana Mozammil Shamsher Khan

is not absolute and certain key mediators, most sig- The ER stress sensors act in concert and their mutual in-
nificantly the transcription factor ATF4 are largely un- teraction plays a pivotal role in determining cell fate. In this
affected, and reciprocally activated. This has important vein, an initial, temporary surge in IRE1 activity in-
downstream effects, for instance increased expression of stigates cell survival, while a preliminary PERK-ATF4 re-
the transcription factor CHOP, as well as modulation of the sponse leads to cell death. The reciprocal control of UPR sig-
apoptosis regulating BCL-2 related molecules. GADD34 naling is illustrated by the divergent effects of the chief me-
(growth arrest and DNA damage-inducible protein), also diators on death receptor 5 (DR5) functioning. This is
referred to as PPP1R15A (protein phosphatase 1 regu- stimulated by the PERK-CHOP cascade, whereas the en-
latory subunit 15A) acts as a phosphatase for p-IF2 with donuclease activity of IRE1 promotes the cleavage of its
the capacity to re-establish the translation of new proteins. mRNA.14 DR5 has a crucial role in controlling the pro-
It is up-regulated by certain transcription factors, not un- liferation of tumor cells, such that the UPR pathway, which
der the control of PERK. Hence, the degree of eIF2 phos- has an overarching effect in determining the fate of cancer-
phorylation is dynamically regulated in the cell and can, ous lesions.
therefore, be manipulated by employing precise activators
or antagonists with the capacity to normalize ER stress in 3. Activating transcription factor 6 (ATF6)
a range of pathological conditions.13 Table 1 gives an ac- The activation of ATF6 is different from IRE1 and
count of the recently identified small molecular com- PERK, as initially its translocation takes place from the ER
pounds, targeting various components of the UPR machi- to the Golgi apparatus. Site-1 and site-2 proteases, located
nery; these are non-toxic and can be administered orally within the membranes of the Golgi apparatus, catalyze the
and circumvent the need for genetic engineering (Table 1). formation of active ATF6 by the process of proteolysis.

TABLE 1. Small molecules/compounds that target ER stress signaling in preclinical disease models

Disease Chemical UPR signaling Main effect Comments

ALS Sephin 1 Inhibition of the stress- ↑p-eIF2, neuroprotection Shown to protect mice neurons from
induced holophosphatase otherwise lethal protein misfolding
PPP1R15A stress
Ischemia Salubrinal Inhibition of PP1, a ↑p-eIF2, neuroprotection Salubrinal penetrates BBB and
induced p-eIF2 phosphatase activates PERK-ATF4 UPR pathway
glutamate enhancing the protein folding capacity
excitotoxicity of the ER
PD Salubrinal Inhibition of Neuroprotection in -synuclein Alpha-synuclein interacts with ER
dephosphorylation of mouse model chaperones and sensitizes neurons to
p-eIF2 UPR-mediated toxicity. Salubrinal
reduces ER stress and attenuates
-synuclein dependent dopaminergic
neurodegeneration
Prion disease GSK2606414 PERK inhibitor ↓ p-eIF2, ↑in synaptic UPR activation and ↑p-eIF2 are seen
proteins, ↓in prion mediated in AD, PD and prion disease resulting
neurodegeneration in transient shut down of protein
translation. An oral compound,
GSK2606414 has been shown to rescue
translational block in hippocampal
slices of prion infected mice
Drug ISRIB Promotes guanine Reverses translational block p-eIF2 levels control compulsive drug
dependence nucleotide exchange induced by p-eIF2 and taking behavior by regulating LTP in
factor eIF2B activity increases cocaine induced LTP the VTA. In a mouse model decreasing
in VTA dopaminergic neurons its activity increased compulsive
cocaine taking
Cultured Compounds Activate the endogenous Selectively reduce the Small non-toxic compounds that target
cell-based 147 & 263 ATF6 branch of UPR extracellular secretion and the ATF6 arm of the UPR have the
screening independently of IRE1 aggregation of misfolded promise to treat degenerative diseases
and PERK proteins responsible for by ER re-programming.
amyloid diseases
AD: Alzheimer’s disease, ALS: amyotrophic lateral sclerosis, ATF6: activation transcription factor 6, BBB: blood brain barrier, ER:
endoplasmic reticulum, LTP: long term potentiation, PD: Parkinson’s disease, PERK: protein kinase RNA-like ER kinase, p-eIF2:
phosphorylated eukaryotic translation initiation factor 2 alpha, PP1: protein phosphatase 1, UPR: unfolded protein response, VTA:
ventral tegmental area.

11
Endoplasmic Reticulum Stress

ATF6 akin to IRE1 induces gene expression of ER chaper- tochondrial import mechanism is malfunctioning which
ons, ERAD constituents and XBP-1.15 In mammals, ATF6 increases ATFS-1 in the nucleus, causing expression of
expression is controlled by two correlated genes, ATF6 UPR (mt)-linked genes. Furthermore, polymorphisms in
and ATF6, and their vital role is illustrated by the fact that mitochondrial DNA (mt DNA) are connected to UPR (mt)
double deletion causes death in-utero in murine models. and cellular senescence, even though this state of affairs
ATF6 is important for development, and experiments in is not so clear-cut.21 Accordingly, experiments in C. elegans
medaka fish have been helpful in understanding this show that UPR (mt) is intrinsically activated in hetero-
process. In this species, ER stress is involved in the embryo- plasmic strains and this leads to soaring numbers of mt
genesis of the brain and notochord, which is apparently DNA deletions.22 It is an open question as to whether com-
brought about by the increased production of extracellular parable mechanisms exist in mammalian cells, for in-
matrix (EM) proteins essential for organ formation. stance in the aging process. Nevertheless, recent research
Experiments demonstrated that the deficiency of ATF6 demonstrates that activating transcription factor 5 (ATF5)
caused a plummeting of BiP and other ER chaperone levels, performs an analogous function in mammalian mitochon-
retarded the folding and secretion of pro-collagen, and drial stress as does ATFS-1 in C. elegans.23 In this regard,
gravely impaired the formation of vital organs.16 further studies are warranted to uncover functional con-
nections of the ATF5-dependent signaling to those of mi-
ER REPROGRAMMING-AN AREA OF FURTHER tochondrial degradation pathways activated in neuro-
STUDY degenerative disorders like Parkinson’s disease.
Moreover, the ER and mitochondria are present in close
During the process of protein quality control, UPR is in- proximity and share approximately 20% of their membranes.
volved in the extrusion to the extracellular space of pro- The MAM enables actual, physical transfer of stimuli be-
teins with a high propensity for aggregation. These poly- tween the two organelles and also facilitate chemical sig-
peptides are often misfolded and accumulate in tissues as naling (Ca++, ROS), an interaction that is gaining primacy
soluble fibrillary compounds, seen in a variety of diseases in understanding processes vital for cell survival. In hu-
typified by amyloid build-up. Activated UPR can increase man degenerative diseases increased oxidative stress is
the level of ER chaperones, for example the protein ERdj3; present which entails mitochondrial formation of reactive
it therefore controls misfolded, aggregate-prone protein oxygen species. Current research has shown that YME1L,
secretion at the cell surface while coordinating this with the a protease resident on the inner mitochondrial membrane
process of proteostasis inside the cell.17 Misfolded trans- is especially susceptible to ROS with the ensuing decreased
thyretin (TTR) is an aggregate-prone protein, and ATF6 capability for handling important mitochondrial proteins
signaling is able to prevent amyloid formation and offset during cell stress. YME1L, together with the catalysts
cytotoxicity by decreasing secretion of the mutant TTR.18 AFG3L2 and paraplegin, fits into the group of proteases
In a process called ER reprogramming, recent series of ex- with ATP binding sub-domains (ATP-dependant AAA+
periments identified small molecular compounds that em- proteases), responsible for protein quality control.24 Alter-
ulate the functioning of ATF6 in diminishing the secretion ations or deficiencies in these effectors cause blighted mi-
of amyloid producing proteins. While serving as an im- tochondrial function and result in such human pathologies
portant means of investigating ER stress, these original as spinocerebellar ataxia type 28 and hereditary spastic
chemicals reduce the synthesis of misfolded polypeptides. paraplegia type 7.25 Thus, UPR (mt) is associated with the
Therefore, they are important in the future development development of various diseases, and in this regard dimin-
of new therapeutic agents for human amyloidosis diseases, ished activity of mitochondrial proteases promotes cell
such as Alzheimer’s disease.19 See also Table 1 for further stress by boosting the formation of protein aggregates.
information on these novel compounds.
UNFOLDED PROTEIN RESPONSE IN
MITOCHONDRIAL UNFOLDED PROTEIN NEUROPSYCHIATRIC DISORDERS
RESPONSE
Many human neurodegenerative disorders such as
Mitochondria are vital for cell survival, and as with the Alzheimer's disease (AD), Parkinson’s disease (PD), amyo-
ER have a protein quality control system exemplified by trophic lateral sclerosis (ALS), and Huntington's disease
specific proteases. Unfolded protein response is a con- (HD) have distinctive pathologies typified by the build-up
served response across species and UPR (mt) is as well of misfolded proteins. Clearly, persistent ER stress is pres-
studied in the worm Caenorhabditis elegans. In C. elegans, ent in such conditions and this is verified in experiments
the activating transcription factor associated with stress-1 which manipulate UPR signaling in laboratory disease
(ATFS-1) is a key regulator of UPR (mt) responsible for in- models. Results signify that the role of UPR in these diverse
stigating nuclear transcription of mitochondrial chaper- conditions is multifaceted and depends on several factors
ones and protective proteins.20 ATFS-1 aids in cross-talk such as the sequencing, potency and characteristics of a
between mitochondria and nucleus; it is typically conveyed specific stressful event in disease development.26
to the former, but under conditions of cellular stress the mi-

12
 Ather Muneer and Rana Mozammil Shamsher Khan

1. Unfolded protein response in AD and prion diseases pathway are highly stimulated and a persistent rise in
AD is characterized by the build-up of extracellular ag- phospho-eIF2 decreases the production of synaptic pro-
gregates of amyloid- (A) oligomers and intracellular neu- teins leading to the loss of neurons. Contrarily, decreased
rofibrillary tangles of the hyperphosphorylated tau protein. activity of the PERK or increased expression of the
The cumulative effect of several derangements such as dis- GADD34 phosphatase reduces the level of p-eIF2, result-
rupted synaptic transmission, impaired calcium homeo- ing in improved synaptic functioning. This lends support
stasis, and unrelenting neuroinflammation leads to cel- to the assumption that manipulation of the PERK/p-eIF2
lular degeneration in AD.27 In this regard, studies employ- pathway is a promising target for the discovery of novel
ing cell cultures have shown that the IRE1/XBP1 sub- medications in prion diseases. Current research in prion-
division of UPR has dual function with respect to -amyloid infected mouse brain tissue has been helpful in delineating
toxicity and is either beneficial as in Drosophila or harmful specific microRNAs and DNA segments that are linked to
as in C. elegans.28 In the latter scenario c-jun N-terminal synaptic functioning. In addition to discovering peripheral
kinase (JNK) pathway is activated and leads to amplified disease markers for the timely diagnosis of prion diseases,
assembly of beta amyloid that exacerbates ER stress.29 these results may aid in identifying crucial pre-sympto-
Contrarily, in an AD mouse model, dampening of PERK ac- matic phases in such pathologies.34
tivity decreases the p-eIF2 levels and ameliorates memo-
ry deficits. These experiments point to specific ER signal- 2. UPR in PD, ALS and HD
ing aberrations and also that particular groups of neurons Protective functioning was linked to IRE1 /XBP1 cas-
in discrete brain areas are affected in a time-specific man- cade, but intriguingly the UPR appeared to play a dual role
ner in disease development.30 in neurodegenerative conditions as a deficiency of XBP1
In an effort to delineate the toxicity of A fibrils, inves- unexpectedly enhanced survival in a mouse model of ALS.
tigators have studied the composition of these precipitates Moreover, a lack of XBP1 increased autophagy via the fork-
from other angles. For instance, the oligomers also have head box 01 (FOXO1) transcription factor, enhancing the
non-protein constituents like glycosaminoglycan (GAG) catabolism of misfolded superoxide dismutase 1 (SOD1).35
polysaccharides that may accelerate A aggregation, and In PD where dopaminergic neurons undergo degeneration,
using heparin as a substitute in nuclear magnetic reso- a lack of XBP1 produced dissimilar results according to the
nance spectroscopy has been helpful in defining their rela- age of experimental mice which denoted corresponding al-
tive position in the deposits. Elucidating the molecular ar- terations in UPR-controlled pathways. Accordingly, the
chitecture of A in this way has importance in designing absence of XBP1 during postnatal growth provoked ER
chemicals which may block amyloid build-up in AD. stress which was physiological with defense against neuro-
Remarkably, the biochemical structure of beta amyloid in nal toxicity induced by 6-hydroxydopamine, even as dele-
AD brains is different from in vitro A; furthermore, it may tion of XBP1 in adulthood caused persistent ER stress and
even vary from patient to patient in diverse clinical death of the dopaminergic neurons.36 Additionally, when
sub-types. This warrants further investigation into the salubrinal (an inhibitor of PPP1R15A/GADD34 phospha-
neuropathology of -amyloid oligomers to fulfill the prom- tase) was given to genetically engineered mice over ex-
ise of better therapeutics for AD.31 pressing misfolded -synuclein , p-eIF2 levels were in-
Prion pathologies resulting from self-propagating prion creased, which was neuro-protective, signifying that the
proteins (PrP) are uncommon neurodegenerative dis- PERK pathway contributed to dopamine neuron degen-
orders exemplified by Creutzfeldt-Jakob disease in hu- eration.37
mans and bovine spongiform encephalopathy in animals. In experimental paradigms where an acute neuronal in-
Misshapen PrP accumulates in brain tissue as amyloid jury was produced by lesions of the spinal cord, local deliv-
oligomers resulting in spongiform changes and progres- ery of XBP1 was beneficial, leading to the continued ex-
sive death of neurons. Disease progression is from cell to istence of cells and enhanced locomotion of animals.38 This
cell during PrP replication and the self-associating prop- implied that by fine-tuning IRE1 /XBP1 branch of the
erty of the protein is central to cell damage.32 In prion dis- UPR, novel drugs could be discovered for application in di-
eases, specific sites are present in the mutant protein that verse neurological conditions. Furthermore, XBP1 may al-
promote accumulation, and interestingly, comparable do- so be implicated in crucial neuronal functions, including
mains have been discovered in other polypeptides like the the formation of memories and new learning. Brain-de-
malformed TAR DNA-binding protein 43 (TDP-43) that rived neurotrophic factor (BDNF) is important in the vital
produces cytoplasmic inclusions in ALS. Prion pathologies processes regulating neuronal plasticity and long-term po-
increase our understanding of abnormal protein handling tentiation (LTP), and varying expression of XBP1 is in-
and propagation of transmittable particles in several neu- criminated in this function. LTP is also influenced by the
rodegenerative diseases. In this respect, new investi- phosphorylation state of eIF2 which is controlled by
gations inform us that a process akin to prion diseases may PERK. These observations point to the significance of UPR
be to blame in the cellular accumulation of -synuclein in signaling in memory-related processes, and further stud-
PD.33 ies are needed to elucidate the findings.39
In mouse models of prion diseases, UPR and the PERK Amytrophic lateral sclerosis, a catastrophic disease, is

13
Endoplasmic Reticulum Stress

characterized by the degeneration of -motoneurons in the 3. Unfolded protein response in brain ischemia and epi-
spinal cord and corticospinal motor neurons (CSMNs) in lepsy
the cerebral cortex. Experiments in transgenic mice have Following brain ischemia and stroke, the levels of the ex-
shown that the ubiquitin C-terminal hydrolase-L1 in the citatory amino acid glutamate are increased leading to ex-
CSMNs is particularly vulnerable to ER stress which is in- citotoxicity, injury, and death of neurons. Acting through
duced by the deletion of the ALS-linked gene, Alsin. In this specific receptor types, glutamate increases intracellular
pathology, ER stress and autophagy contribute to the loss calcium and decides neuronal fate. Enhanced ER stress is
of CSMNs, hinting at promising new therapeutic targets.40 linked to hypoxic damage since in experimental paradigms
Furthermore, fresh studies have revealed that ALS and where brain ischemia is induced by cerebral vessel occlu-
frontotemporal dementia are related and have in common sion, hypoxic injury and glutamate toxicity is stalled by
a key genetic variation i.e. the existence of a hexanucleotide Salubrinal which acts as a specific inhibitor of the eIF2
repeat sequence in the gene, C9orf72. Epigenetic mod- phosphatase, incriminating UPR signaling in stroke
ification of the gene function may provide a new under- models.45
standing of the sub-cellular processes fundamental to neu- In epilepsy there is increased electrical activity in the
ronal dysfunction in these ailments.41 The phosphatase, brain leading to recurrent, aberrant neuronal discharges
PPP1R15A/GADD34 which regulates the levels of p-eIF2 and seizures. The characteristic of convulsive activity dif-
is an important therapeutic target in ALS. In this vein, it fers among patients, and in the majority is controllable by
has been demonstrated that the chemical guanabenz is ca- medications. However, chronic temporal lobe epilepsy is of-
pable of prolonging eIF2 phosphorylation and buttress- ten treatment refractory causing ER stress and partic-
ing proteostasis. Nonetheless, guanabenz is an adrenergic ularly stimulating the IRE1 pathway, adding to injury.46
agonist resulting in hypotension and consequently is of lit- This proposes that the mitigation of ER stress is of possible
tle utility in actual patients. Further testing was in- value in reducing damage to neurons in epilepsy, warrant-
strumental in the recognition of a novel compound, ing further exploration of this avenue.
Sephin1, which selectively inhibited a holophosphatase ca-
pable of modulating the PERK/p-elf2 pathway and re- 4. UPR in major psychiatric disorders
instated proteostasis. In experimental conditions in the al- Admittedly, psychiatric disorder studies on the role of
tered SOD1-ALS mouse model, sephin1 showed neu- ER stress and UPR activation are in short supply. Bipolar
ro-protective properties, improved behavior, and had no disorder (BD) is a major mood disorder exemplified by epi-
significant adverse effects. Further, this molecule averted sodes of depression and mania; its neurobiology is multi-
demyelination in the Charcot-Marie-Tooth disease model faceted and linked to other mental and physical disorders.
produced by the misfolded myelin protein zero.42 New re- Studies employing BD patient-derived blood cells revealed
search should demonstrate whether sephin1 or analogous that the response to ER stress activating compounds like
chemicals would be of value in ALS and other human pro- tunicamycin or thapsigargin was abnormal compared with
tein misfolding disorders. controls suggesting compromised cellular reaction to
Investigations into prototypes of HD revealed that the stress. Lithium is the prototype mood stabilizer widely
silencing of XBP1 was neuro-protective by decreasing the used in the management of BD and recent data has demon-
aggregation of the misshapen Huntingtin protein (Htt) and strated that this medication is involved in the expression
promoting the existence of neurons. Similar to ALS, in HD, of genes which contribute to maintaining ER functioning.
a lack of XBP1 increased ER related compensatory mecha- Together, this supports the premise that ER stress and
nisms like autophagy and up-regulated FOXO1 expression. UPR processes are important targets in the treatment of
Moreover, it has been revealed lately that the ubiq- BD.47 Moreover, found within the ER and acting together
uitin-specific protease 14 was instrumental in the catabo- with mitochondria is the sigma-1 receptor (Sig-1R) which
lism of misfolded Htt by recruiting IRE1 and modulating is targeted by a range of psychotropic medications. A MAM
the proteasome function, further adding to the complexity residing chaperone, the Sig-1R is a key mediator and plays
of HD pathology.43 The accumulation of misfolded Htt dif- an important role under stressful conditions by modulat-
ferentially occurred in specific cellular areas like the cyto- ing inter-organelle Ca++ signaling. It facilitates the pas-
plasm and the nucleus, and lately it has been demonstrated sage of stress signals from the ER to the nucleus via numer-
that Htt-polymers were found along the nuclear mem- ous receptors, ion channels, kinases, and regulatory pro-
brane, possibly interfering with the physiological trans- teins present in the ER, MAM, cytosol, and nucleus. Thus,
port of transcription factors and mRNA. Additionally, ex- this diverse regulator modulates bioenergetics, redox bal-
pression of TDP-43, which is related to the development of ance, UPR, and cytokine signaling. In the neurons, it par-
ALS, also influenced this mechanism.44 This implies that takes in dendrite outgrowth, synaptogenesis, and LTP and
nucleocytoplasmic variations in HD and other human pro- appears to play a vital role in neuropsychiatric diseases;
tein misfolding pathologies need further investigation. however, this awaits further delineation.48
In BD, a number of studies utilizing patient-derived lym-
phoblastoid cell lines or peripheral leucocytes have re-
vealed anomalous reactions by the ER to induced stress.

14
 Ather Muneer and Rana Mozammil Shamsher Khan

In a seminal study in BD patients’ B-lymphocytes, So et al.49 ditions are described and the pivotal role of the endoplas-
reported lowered expression of XBP1 and CHOP genes mic reticulum is highlighted. The mitochondrial oper-
when stimulated by thapsigargin and tunicamycin. These ations are regulated through the lipid raft like ER mem-
observations were strengthened by another study which branes, or MAM, and these, in addition to controlling mi-
found an increase in several proteins concerned in UPR tochondrial shape and motility, influence bioenergetics
(p-eIF2, GRP78, XBP1 and CHOP) in leucocytes treated and redox balance. Besides, the MAM plays a critical role
with tunicamycin from controls, but not in those from bipo- in cellular adaptation and survival via modulating ER
lar cases. There was more apoptosis of cells in cases com- stress, proteostasis, inflammasome signaling, and apoptosis.
pared to controls, and this phenomenon was greater in The ER associated transcription factors, chaperones, and
chronic patients, signifying that disease progression in- catalysts have a pivotal function in this process, with the
creased vulnerability to ER stress.50 In their study, Hayashi failure of the unfolded protein response causing cellular
et al.51 treated BD patient-derived lymphoblastoid cell loss through accumulation of toxic protein aggregates.
lines with thapsigargin and compared these to controls, Miscommunication between vital cellular organelles like-
showing a reduction in the expression of XBP1 and GRP94 ly underlies not just neuropsychiatric disorders, but also
in these cases. A mutation caused by a single nucleotide disorders of aging, metabolic conditions, and cancer. With
polymorphism (SNP; −116C/G; rs2269577) in the pro- respect to the development of principal psychiatric dis-
moter region of the XBP1 gene deregulated feedback loop orders a supposed cascade of events is as follows:
in the ER response and was found to be linked to BD.52 An a) Severe or persistent ER stress is linked to increased
interesting study examined RNA sequences in peripheral ROS and Ca++.
circulating leucocytes in healthy controls, lithium-re- b) Up-regulation of transcription factors (CHOP) and
sponsive cases, and lithium-non-responsive patients. kinases (JNK) via activation of the pro-apoptotic branch of
Discrepant gene analysis has showed that in BD, the clin- the UPR.
ical response to lithium is modulated by a gene network c) Failure of UPR leads to the accumulation of protein
that regulates ER stress.53 Generally, the above findings aggregates.
implied that in BD, the compensatory reaction of cells to d) The latter cause stimulation of the inflammasome and
ER stress was blighted and this limited their survival un- increased inflammatory signaling through pro-inflam-
der stressful conditions. Interestingly, the most commonly matory cytokines.
employed mood stabilizers, lithium and valproate, ap- e) Activation of proapoptotic caspases with enhanced
peared to possess protective properties, since these en- apoptosis of neurons.
hanced the resilience of cells to ER stress.54 Fig. 4 schematically depicts this likely model of disease
Autophagy represents a cellular process intended to progression while identifying new targets for the develop-
re-establish homeostasis or assign cells to degradation in ment of novel therapeutic agents (Fig. 4).
the wake of stressful events. In the course of autophagy,
misfolded protein aggregates, membranous elements, and CONCLUSION
sub-cellular organelles are degraded and the resulting mo-
lecular compounds are reprocessed. Two pivotal cascades To reduce the load of unfolded or misfolded proteins and
controlling autophagy-related genes are the phosphatidy- prevent abnormal protein aggregation, proteostasis en-
linositol 3-kinase which is activated, along with the simul- tails dynamic coordination between the efficient folding of
taneous inhibition of mTOR kinase. An intricate relation- newly synthesized proteins, quality control, and degrada-
ship is at work governing autophagy, ER stress, and mi- tion mechanisms. Chaperones are an essential first line de-
tochondrial function. In this respect, the effectors of UPR fense in this process since they recognize non-native con-
trigger autophagy and influence mitochondrial function by formations of polypeptides, which are then consigned to re-
modulating the actions of Parkin. On the flip side, Parkin folding through the UPR. In the instance of a failure of this
is a controller of mitochondrial function and is required to protective process, degradation mechanisms —ubiquitin
destine non-functioning mitochondria to mitophagy.55 proteasome pathway and autophagy are activated.
Recently, a study observed that autophagy was decreased Complementary in their mode of action, these pathways
in schizophrenia and MDD.56 In this vein, a recently pub- act as a subsequent step to restore proteostasis. When the
lished paper conjectured that in psychiatric disorders, dys- proteasome is defective or saturated, or if there is an excess
functions in cell biology were found, however, abnormal- of ROS, the accumulation of misfolded proteins occurs lead-
ities in autophagy and mitochondrial functioning were of ing to the formation of both toxic soluble oligomers and larg-
crucial significance.57 er aggregates that can then be eliminated by autophagy.
However, in several neuropsychiatric disorders, autopha-
A CELLULAR PATHOGENIC MODEL OF MAJOR gic vacuoles (autophagosomes or autophagolysosomes) ac-
PSYCHIATRIC DISORDERS cumulate suggesting lysosomal dysfunction. Due to the im-
pairment of the autophagic pathway, misfolded proteins
In the ongoing discussion regarding the most pertinent and aggregates are not cleared from the cells resulting in
aspects of cellular functioning under pathological con- cell death.

15
Endoplasmic Reticulum Stress

dividual branches of UPR and some of the recently identi-

fied chemicals with specific reference to CNS are summar-
ized in Table 1, with the caveat that these small non-toxic
molecules have been studied in preclinical models. More-
over, this catalog is essentially interim as many studies are
in progresss and are yet to be published, signifying that
novel compounds possessing the ability to fine tune the
function of the ER will likely be added to this list. Targeting
the MAM and the processes that involve protein degrada-
tion pathways and the inflammasome are valid options in
the development of new therapeutic agents for essentially
recalcitrant human diseases.
In summary, the ER stress response is closely associated
with mitochondrial functioning; the failure of proteostasis
leads to the formation of protein aggregates that induce an
immune response through intracellular inflammasome
formation, most importantly the NLRP3 inflammasome.
The signals that provoke aberrant cellular responses in-
clude the buildup of ROS, abnormal Ca++ ionic fluxes and
pro-inflammatory cytokines. Under pathological conditions,
compensatory homeostatic mechanisms fail and pro-apop-
totic caspases are triggered with increased loss of cells. A
FIG. 4. A cellular pathogenic model of disease development in ma- better understanding of these complicated mechanisms is
jor psychiatric disorders. Major psychiatric disorders including
essential to find cures for numerous human diseases, in-
mood disorders, psychotic disorders and neurodegenerative dis-
cluding neuropsychiatric disorders.
orders are characterized by increased endoplasmic reticulum
(ER) stress. ER chaperones act as first line of defense against un-
folded or misfolded proteins, but accumulation of non-natively FUTURE PERSPECTIVE
conformed polypeptides in the ER lumen activates other compen-
satory mechanisms. ER and mitochondria work in close unison As evidence accumulates, it is becoming clear that UPR
through the mitochondria-associated ER membranes, stimulat- (ER) and UPR (mt) play a pivotal role in the advancement
ing the mitochondrial unfolded protein response (UPR mt). of numerous human diseases including neuropsychiatric
However, in cellular stress increased generation of reactive oxy- ailments, such that targeting this pathway is a primary ob-
gen species (ROS) and build up of intracellular calcium ions fur- jective in the development of novel therapeutic agents. In
ther exacerbates ER/mt stress. During proteostasis, unfolded/ this regard, the modulation of the ER - related quality con-
misfolded proteins are degraded via the ubiquitin-proteasome
trol mechanisms via activation of protective and adaptive
system but when the latter gets saturated, toxic oligomers or larg-
UPR responses, and/or the inhibition of the apoptotic path-
er aggregates accumulate, which can then be got rid of through
ways emerge as significant strategies.58 Drawing on chem-
lysosomal autophagic mechanisms. Since lysosomal dysfunction
is present in many neuropsychiatric diseases, accumulated pro- ical chaperones such as 4-phenylbutyric acid (PBA), taur-
tein aggregates acting as danger associated molecular patterns oursodeoxycholic acid (TUDCA) or trimethylamine oxide
cause activation of the inflammasome leading to inflammatory- (TMAO) may be beneficial as these compounds improve ER
immune signaling and ultimately increased apoptosis of neurons. folding capacity and stabilize protein conformation.59 In an
This cascade is responsible for increased damage to neurons and AD mouse model, PBA was shown to enhance ER function-
its further elucidation can result in the development of novel ther- ing, thwart A accumulation, and avoid the loss of dendritic
apeutic agents for otherwise recalcitrant neuropsychiatric diseases. spines and memory.60 TUDCA, a taurine-conjugated de-
rivative from ursodeoxycholic acid was found to prevent A
production in the cortex and hippocampus of APP/PS1 mice
The ER, a vital sub-cellular component, acts in concert through the regulation of APP processing, salvaging neu-
with other organelles, most importantly the mitochondria rons, and improving memory.61 Although experimented
through the MAM and this interaction either leads to cell upon less often, the chemical chaperone TMAO has been
survival or apoptosis. Indeed, crucial physiological proc- found to be more efficient than PBA and TUDCA in enhanc-
esses including regulation of the metabolism, inflammation, ing protein folding, decreasing buildup of protein ag-
neuronal plasticity, cognition, and aging are all modulated gregates, and preventing apoptosis; hence it can be consid-
in an intricate manner. Therefore, it comes as no surprise ered a promising therapeutic strategy for protein misfold-
that numerous human diseases including neuropsychi- ing disorders.62
atric disorders are caused by dysfunction in the essential Ca++ is a vital player in inter-organelle communication
processes alluded to above. This understanding has lead through the MAM and many catalysts/chaperones do not
to the development of specific compounds which target in- work properly when Ca2+ homeostasis is blighted. Targeting

16
 Ather Muneer and Rana Mozammil Shamsher Khan

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