Autophagy

ISSN: 1554-8627 (Print) 1554-8635 (Online) Journal homepage: http://www.tandfonline.com/loi/kaup20

Interplay of endoplasmic reticulum stress and

autophagy in neurodegenerative disorders

Yu Cai, Jyothi Arikkath, Lu Yang, Ming-Lei Guo, Palsamy Periyasamy & Shilpa
Buch

To cite this article: Yu Cai, Jyothi Arikkath, Lu Yang, Ming-Lei Guo, Palsamy Periyasamy & Shilpa
Buch (2016) Interplay of endoplasmic reticulum stress and autophagy in neurodegenerative
disorders, Autophagy, 12:2, 225-244, DOI: 10.1080/15548627.2015.1121360

To link to this article: http://dx.doi.org/10.1080/15548627.2015.1121360

Published online: 22 Feb 2016.

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 AUTOPHAGY
2016, VOL. 12, NO. 2, 225–244
http://dx.doi.org/10.1080/15548627.2015.1121360

REVIEW

Interplay of endoplasmic reticulum stress and autophagy

in neurodegenerative disorders
Yu Caia, Jyothi Arikkatha,b, Lu Yanga, Ming-Lei Guoa, Palsamy Periyasamya, and Shilpa Bucha
a
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA; bDevelopmental
Neuroscience, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, NE, USA

ABSTRACT ARTICLE HISTORY

The common underlying feature of most neurodegenerative diseases such as Alzheimer disease (AD), Received 6 February 2015
prion diseases, Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS) involves accumulation of Revised 1 September 2015
misfolded proteins leading to initiation of endoplasmic reticulum (ER) stress and stimulation of Accepted 12 November 2015
the unfolded protein response (UPR). Additionally, ER stress more recently has been implicated in the KEYWORDS
pathogenesis of HIV-associated neurocognitive disorders (HAND). Autophagy plays an essential role in the autophagy; alzheimer
clearance of aggregated toxic proteins and degradation of the damaged organelles. There is evidence that disease; amyotrophic lateral
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autophagy ameliorates ER stress by eliminating accumulated misfolded proteins. Both abnormal UPR and sclerosis and HIV-associated
impaired autophagy have been implicated as a causative mechanism in the development of various neurocognitive disorders; ER
neurodegenerative diseases. This review highlights recent advances in the field on the role of ER stress stress; neurodegenerative
and autophagy in AD, prion diseases, PD, ALS and HAND with the involvement of key signaling pathways disorders; prion diseases;
Parkinson disease
in these processes and implications for future development of therapeutic strategies.

Introduction ER stress signaling pathways and the autophagic mechanism(s)

Neurodegenerative disorders are characterized by progressive
loss of neuronal functions that are closely associated with loss/
dysfunction of neuronal cells. Emerging evidence suggests that
accumulation of exogenous or abnormal misfolded proteins
leads to a state of endoplasmic reticulum (ER) stress in neu-
rons, contributing to the salient pathology associated with neu-
rodegeneration. In order to restore homeostasis within the ER
there occurs sequential activation of the unfolded protein
response (UPR) involving translational attenuation of global
protein synthesis, transcriptional induction of genes function-
ing as ER chaperones, and the ER-associated degradation
(ERAD) of aggregated proteins ultimately leading to autoph-
agy.1,2 Autophagy is an essential catabolic mechanism that
delivers misfolded proteins and damaged organelles to the lyso-
some for degradation.3 Maintaining basal levels of autophagic
activity is critical for postmitotic neurons that are unable to dis-
pose of aggregated proteins via cell division.4 As a result,
increased dependence of neurons on a higher threshold of con-
stitutive, basal levels of autophagy thus renders these cells more
vulnerable to impairments in autophagy, a key feature underly-
ing most neurodegenerative diseases. Accumulating evidence
suggests that in chronic neurodegenerative disorders, persistent
ER stress often results in stimulation of autophagic activities,
likely as a compensatory mechanism, to relieve ER stress; how-
ever, in the face of impaired UPR or autophagy, there is ineffi-
cient clearance of the accumulated proteins, which in turn,
leads to the development and progression of neurodegenera-
tion. This review is an attempt to provide a survey of the major
and their interplay in the development and progression of neu-
rodegenerative diseases such as AD, prion diseases, PD, ALS
and HAND.
ER stress and UPR
ER stress is a pathological state that involves the aberrant
aggregation of misfolded proteins, which in turn, results in the
UPR that is initially expected to rescue cells from the stress and
restore homeostasis within the ER.1 The ER stress stimuli in
neurodegenerative disorders include accumulation of exoge-
nous viral proteins,5 aggregation of mutant endogenous pro-
teins6 and depletion of ER calcium stores via ITPR (inositol-
1,4,5-trisphosphate receptor)7,8 and RYR (ryanodine receptor).5
Chaperones within the ER, such as HSPA5 (heat shock 70 kDa
protein 5 [glucose-regulated protein, 78kDa]), and CALR (cal-
reticulin), require high levels of [Ca2C]ER for binding to paired
anionic amino acids to carry out the function of protein folding
(Fig. 1).9,10 Thus, depletion of ER calcium store renders ER-res-
ident chaperones inactive for proper protein folding processes,
resulting in the accumulation of misfolded proteins.
In the central nervous system, the UPR is initiated by 3
major cascading transmembrane sensors: a) EIF2AK3 (eukary-
otic translation initiation factor 2-a kinase 3), b) ERN1 (endo-
plasmic reticulum to nucleus signaling 1) and c) ATF6
(activating transcription factor 6). 11 The most abundant ER
chaperone, HSPA5 plays an essential role in initiation of the
UPR by 3 major sensors.11 The ER-luminal domain of

CONTACT Shilpa Buch sbuch@unmc.edu Durham Research Center Room 8011, 985880 Nebraska Medical Center, Omaha, NE, 68198, USA.
Color versions of one or more figures in this article can be found online at www.tandfonline.com/kaup.
© 2016 Taylor & Francis Group, LLC
 226 Y. CAI ET AL.
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Figure 1. ER stress and UPR pathways in neuronal cells. Pathological accumulation of misfolded proteins and/or depletion of ER calcium store via activation of ITPR and
RYR leads to ER stress. Dissociation of HSPA5 from 3 ER stress sensors, EIF2AK3, ERN1 and ATF6, results in phosphorylation of EIF2AK3 and ERN1 and translocation of
ATF6 to the Golgi apparatus. Activated EIF2AK3 is a serine/threonine protein kinase that phosphorylates EIF2S1. p-EIF2S1 (phosphorylated EIF2S1) inhibits global protein
synthesis but selectively upregulates ATF4, PPP1R15A, DDIT3 and ATF3. PPP1R15A provides a negative feedback by dephosphorylating p-EIF2S1. ERN1 cleaves XBP1
mRNA; the spliced form of XBP1 encodes the XBP1 protein. XBP1 increases the expression of genes encoding ER chaperones, ERAD proteins and lipid synthesis to restore
the capacity of protein folding. ATF6 is translocated to the Golgi apparatus where it is cleaved by MBTPS1 and MBTPS2, and cleaved ATF6 stimulates the expression of ER
chaperones and ERAD proteins. Apoptosis will ensue if upregulation of ER chaperones and ERAD proteins fails to rescue ER stress.

EIF2AK3, ERN1 and ATF6 interacts with HSPA5 to suppress
ER stress under physiological conditions (Fig. 1). Following cel-
lular stress and accumulation of unfolded proteins, there is dis-
sociation of HSPA5 from the ER sensor proteins, leading to the
activation of ER stress sensors.12
EIF2AK3 is a serine/threonine protein kinase that is acti-
vated by dimerization and trans-autophosphorylation following
dissociation from HSPA5 (Fig. 1).13 Phosphorylation of EIF2S1
(eukaryotic translation initiation factor 2, subunit 1 a, 35kDa)
mediated by active EIF2AK3 causes a shift in the open reading
frames from the true translation initiation site to a site
upstream of the coding region of ATF4 (activating transcrip-
tion factor 4) as well as ATF3 (activating transcription factor
3), DDIT3 (pro-apoptotic transcription factor, DNA-damage-
inducible transcript 3) and PPP1R15A (protein phosphatase 1,
regulatory subunit 15A), a cofactor for PPP1 (protein phospha-
tase 1) that serves as a negative-feedback regulator of EIF2S1
phosphorylation.14,15 Activation of EIF2AK3 therefore attenu-
ates global translation of proteins while paradoxically stimulat-
ing the expression of stress response genes. However, if the
UPR fails to rescue neurons from ER stress, ensuing ER stress
culminates in activation of apoptosis.16
ERN1 is a ubiquitous serine/threonine kinase (Fig. 1). Simi-
lar to EIF2AK3, following dissociation of HSPA5, the kinase
domain of ERN1 is activated. However, unlike EIF2AK3, ERN1
contains a C-terminal endoribonuclease domain that is also
activated following accumulation of the unfolded proteins.17
The endoribonuclease domain is responsible for the splicing of
the mRNA encoding the transcriptional factor XBP1 (X-box
binding protein 1).17 The protein XBP1 translated from XBP1s
(spliced form of XBP1 mRNA) in turn stimulates the expres-
sion of ER chaperones, ERAD proteins and lipid synthesis to
restore protein folding capacity within the ER.18
ATF6 is also an ER stress transmembrane sensor belonging
to a family of bZIP transcription factors (Fig. 1).19 In response
to the UPR, HSPA5 dissociation releases ATF6 from the ER
membrane allowing it to translocate to the Golgi, where it is
cleaved by proteolytic cleavage to a soluble form resulting in its
trafficking into the nucleus.20-22 Following translocation into
the nucleus, ATF6 functions as a transcription factor responsi-
ble for recovery from acute stress with tolerance to chronic
stress by inducing the expression of ER chaperone genes such
as those encoding HSPA5 and PDI (protein disulfide isomer-
ase) folding enzymes and the ERAD components.23
Overall, the activation of ER stress leads to attenuation of
global protein synthesis, induction of ER chaperones to
increase the capacity of the ER for protein folding and induc-
tion of ERAD elements to decrease the ER protein load.18
 AUTOPHAGY 227

Autophagy target of rapamycin [serine/threonine kinase] complex 1) and,

reciprocally, activation of AMPK (AMP-activated protein
Macroautophagy (hereafter autophagy) is a tightly regulated
kinase),32 both of which lead to activation of the ULK1 (unc-51
catabolic pathway for lysosomal degradation of cytoplasmic
like autophagy activating kinase 1) complex by changing the
organelles or cytosolic components and the recycling of the
phosphorylation state of certain components in the complex.33
resulting macromolecules.24 Homeostasis of autophagic activi-
The activated ULK1 complex initiates vesicle nucleation by
ties in the cytoplasm is critical for maintenance of neuronal
translocating the BECN1 (Beclin 1, autophagy related)-contain-
functioning. There is increasing evidence that failure in clearing
ing core multiprotein complex and the class III phosphatidyli-
the aggregated proteins or impaired organelles contributes to
nositol 3-kinase from the cytoskeleton to sites of phagophore
programmed cell death or apoptosis.25 Intriguingly, abnormal
assembly.33-36 Vesicle nucleation is followed by membrane
autophagic activity has been described in AD,26 HD,27 PD28
elongation. In the process of elongation of autophagic mem-
and Creutzfeldt-Jakob disease (CJD).29
brane, ATG12 (autophagy-related 12) conjugated to ATG5
Autophagy is initiated by the sequestration of targeted sub-
(autophagy-related 5) positively regulates the conjugation of
strates within double-membrane vesicles termed phagophores
phosphatidylethanolamine to MAP1LC3B (microtubule-associ-
that mature into autophagosomes.30 Prior to autophagosome
ated protein 1 light chain 3 b),37,38 followed by the conversion
fusion with the lysosome and degradation of the sequestered
of MAP1LC3B from soluble MAP1LC3B-I into autophagic ves-
cargo, autophagy undergoes a series of key steps including acti-
icle-associated MAP1LC3B-II.39 MAP1LC3B-II stably binds to
vation by signal transduction, phagophore nucleation, mem-
the phagophore and autophagosome membranes.40 Finally, the
brane elongation, lysosomal fusion and cargo degradation
autophagosomes fuse with the lysosome for degradation of the
(Fig. 2).31 Stress stimuli, such as starvation, oxidative stress,
sequestered cargo.41 Moreover, endocytic recycling is a
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and ER stress, result in inhibition of MTORC1 (mechanistic

Figure 2. The autophagic cascade in neurodegenerative disorders. Stress stimuli associated with neurodegenerative disorders inhibits MTORC1, resulting in activation of
the ULK1 complex. The ULK1 complex can also be activated by AMPK. The ULK1 complex initiates vesicle nucleation by translocating BECN1 and PtdIns3K to phagophores.
To elongate the membrane from the phagophore assembly site (PAS), The ATG12–ATG5 conjugate regulates the conjugation of PE to MAP1LC3B, resulting in conversion
of MAP1LC3B from soluble MAP1LC3B-I into phagophore and autophagosome-associated MAP1LC3B-II. Once the autophagosome is formed, it fuses with a lysosome for
degradation of its sequestered cargo.
 228 Y. CAI ET AL.
complicated process correlated with endocytic uptake to regu-
late the components of the plasma membrane. Regulation of
endocytic recycling involves various molecules such as RAB1A,
RAB11, RAB8, RAB22, ARHGAP26 (Rho GTPase activating
protein 26), EHD1 (EH-domain containing 1), and MICALL1
(MICAL-like 1).42-47 Recent evidence also demonstrates that
recycling endosomes promote autophagy.48
Autophagy is highly conserved in all types of eukaryotic cells
and is essential for the regulation of basic cellular processes
such as growth and apoptosis. Among all the other cell types,
neurons exhibit higher basal levels of autophagy. This could
likely be attributed to their structure and function: (1) Neurons
are the largest cells in the human body (based on their length)
and have highly specialized structures such as axons and den-
drites that are the sites for synthesis of macromolecules includ-
ing proteins, RNA and lipids. Appropriate delivery and
degradation of these macromolecules is essential for homeo-
static maintenance of normal synaptic growth and activity. (2)
Neurons are nondividing cells that are extremely sensitive to
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accumulation of toxic aggregates compared to the other mitotic
cells. (3) Neurons require higher energy for execution of their
normal functions. In summary, owing to the increased suscep-
tibility of neurons to genetic/environmental insults, they are
endowed with tightly regulated and effective intrinsic mecha-
nisms such as autophagy, to execute their normal functions
during a pathological insult. Protein quality control by auto-
phagy is thus an essential attribute for neuronal survival and
functioning. Dysfunction of the autophagic activities impedes
synaptic development,49 hampers axonal function and could
underlie the onset and progression of various neurodegenera-
tive disorders.4 Paradoxically, however, once the UPR and
autophagy responses are unable to eliminate the damaged pro-
teins or organelles effectively, neurons become highly suscepti-
ble to the diseases of protein aggregation underlying the
neurodegenerative diseases.
ER stress and autophagy
Emerging studies also demonstrated a mechanistic link between
the ER stress and autophagy, in which the activation of
EIF2AK3 is essentially required due to the misfolded protein
accumulation shown in various diseases to induce auto-
phagy.50,51 Furthermore, the UPR downstream mediators of
EIF2AK3 such as ATF4 and DDIT3 were also reported to guide
the induction of autophagy gene transcription such as with
BECN1, MAP1LC3B, ATG5, ATG7 and ATG12 in response to
amino acid starvation or ER stress.52 Hypoxic microenviron-
ments also activate EIF2AK3- and ATF4-DDIT3 signaling,
which is ultimately involved in the regulation of MAP1LC3B
and ATG5 proteins to induce autophagy.53,54 Another arm of
ER stress, involving ERN1, is also involved in autophagy induc-
tion via activating AMPK in response to nitric oxide.55 Alterna-
tively, ERN1 induces autophagy through dissociation of
BECN1 from its binding with the anti-apoptotic protein BCL2
(B-cell CLL/lymphoma 2)56,57 via MAPK8 (mitogen-activated
protein kinase 8)-mediated phosphorylation of BCL2.58,59 Fac-
tors downstream of ERN1, such as XBP1, also play an essential
role through an interaction with FOXO1 (forkhead box O1) in
the negative feedback loop of ER stress-mediated autophagy.60-
62
In addition, the soluble ATF6 formed after proteolytic cleav-
age under ER stress can upregulate the expression level of
DAPK1 (death-associated protein kinase 1).63,64 The increased
DAPK1 phosphorylates BECN1 leading to the effective dissoci-
ation from its negative regulator BCL2, thereby triggering
autophagy (Fig. 3).65 Overall, the misfolded/aggregated proteins
induce ER stress and shackle the autophagy functions in vari-
ous diseases including neurodegenerative diseases.
Intracellular protein aggregation is one of the salient features
underlying various neurological diseases such as AD and
PD.66,67 The balance between protein generation and degrada-
tion is crucial for protein homeostasis. Intriguingly, while most
of the aggregated proteins result in the common endpoint of
neuronal impairment, the mechanism of action of each of the
aggregated proteins is distinct. For instance, aggregated Ab
(b-amyloid) that is cleaved from its membrane-bound precur-
sor APP (amyloid precursor protein), is a primary source of ER
stress in AD,68,69 whereas in PD dysfunction appears to result
from the accumulation of Lewy bodies and intracellular inclu-
sion bodies containing diffuse deposits of misfolded SNCA/
a-synuclein (synuclein, a [non A4 component of amyloid pre-
cursor]).67 ER stress is likely a secondary response due to oxida-
tive stress and/or inflammation mediated by the aggregates.70-73
Taken together, based on the nature of the disease, the
sequence of events mediated by the aggregated proteins can be
very different. For example, in the case of AD, Ab is the pri-
mary source of ER stress whereas in PD, the accumulated
SNCA first induces cellular responses, which, in turn mediate
the secondary ER stress leading to disease pathogenesis.
Similar to the diversity of signaling events observed in
AD and PD, differences in the tissue responses in the accu-
mulation of aggregated proteins in the autosomal dominant
mutations in PD and AD also show striking differences.
Genetic mutations (accounting for autosomal-dominant
AD) in APP, PSEN1 (presenilin 1) or PSEN2 (presenilin 2)
divert the normal processing of APP toward the amyloido-
genic phenotype, leading in turn to enhanced production
and deposition of total Ab and Ab peptides, that have a
greater tendency to aggregate and mediate disease patho-
genesis.74 Unlike AD wherein augmented production of
aggregated proteins plays a major role in disease pathogene-
sis, in the autosomal dominant mutations of PD such as
SNCA and LRRK2 (leucine-rich repeat kinase 2), protein
degradation pathways are impeded, leading to accumulation
of faulty aggregated proteins. It has been well documented
that mutant SNCA impedes autophagy by inhibiting the
GTPase RAB1A, whereas mutations in LRRK2 hinder the
autolysosomal degradation pathways in the late stage of
autophagic activity.75,76 Intriguingly, therefore, while accu-
mulation of aggregated protein response underlies both the
autosomal dominant mutant form of AD and PD, the
mechanism(s) by which the protein aggregation occurs
(impaired protein degradation in PD vs. increased protein
production in AD) leading to disease pathogenesis, is
unique for each disease. A better understanding of the tis-
sue response in mediating the aberrant protein aggregation
is thus critical in dissecting the mechanism(s) underlying
disease pathogenesis and for future development of thera-
peutic targets.
 AUTOPHAGY 229
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Figure 3. The interplay between the UPR and autophagy. EIF2AK3-EIF2S1 signaling induces the expression of various autophagy-related proteins via ATF4 and DDIT3.
ERN1 triggers autophagy through activation of AMPK and dissociation of BECN1 from BCL2 via MAPK8-dependent phosphorylation of BCL2. Conversely, XBP1 that acts as
the downstream mediator of ERN1 provides negative feedback for autophagy by promoting degradation of FOXO1. Upregulation of DAPK1 induced by cleaved ATF6
phosphorylates BECN1 and leads to dissociation of BECN1 from BCL2, resulting in enhanced autophagic activities.

Alzheimer disease and other tauopathies level of HSPA5 in neurons, HSPA5 plays a neuroprotective role
against ER stress-associated cell death by suppressing oxidative
AD, one of the most common neurodegenerative diseases in
stress and maintaining calcium homeostasis.83 Intriguingly,
the elderly, is characterized clinically as an ongoing cognitive
unlike Ab, mutations of PSEN1 inhibit major ER stress sensors
impairment with typical pathogenic deposits of neurofibrillary
including HSPA5, EIF2AK3, ERN1 and ATF6, rendering neu-
tangles containing hyperphosphorylated MAPT/tau (microtu-
rons vulnerable to ER stress stimuli.84,85 Thus, the UPR plays a
bule-associated protein tau) and extracellular accumulations of
neuroprotective role in AD but can be disrupted by either accu-
Ab plaques.77 Ab is the cleaved product released from its pre-
mulation of Ab or PSEN1 mutations, possibly sharing a com-
cursor protein, APP, following exposure to BACE1/b-secretase
mon pathway—release of calcium from the ER into the cytosol
and g-secretase.78 The complex of g-secretase, composed of at
via ITPR and RYR. UPR activation is an early event in the AD
least PSEN1 and PSEN2 in the ER, cleaves APP to Ab of vary-
brain, which enhances autophagy but not the ubiquitin protea-
ing lengths—Ab40 and Ab42. Genetic mutations in APP, PSEN1
some system in the phosphorylated EIF2AK3-positive neurons
and PSEN2 account for autosomal-dominant AD.79 Another
via increasing MAP1LC3B, suggesting that autophagy is the
salient feature of AD is pathological aggregation of the MAPT
predominant pathway for degradation of Ab or APP.86 Insuffi-
protein.80 MAPT is an axonal cytosolic protein for the stabiliza-
cient autophagic function is also suggested to play a significant
tion of the microtubule network, but it becomes hyperphos-
role in the progression of AD.87 The study by Pickford et al.
phorylated and aggregated within neurons in the form of
demonstrated substantial loss of BECN1 in the midfrontal cor-
neurofibrillary tangles.80
tex of AD brains in the disease progression.87 Intriguingly,
UPR and autophagy play an important role in protecting
studies by this group also demonstrated that genetic reduction
neurons against accumulation of Ab and PSEN1 mutations in
of BECN1 expression results in increased deposition of Ab
the familial form of AD. PSEN1 mutations and intracellular
deposition and synaptic loss and, reciprocally, increasing
Ab, but not extracellular Ab, have been reported to trigger ER
BECN1 expression through administration of lentivirus allevi-
stress in neurons by releasing ER calcium into the cytosol via
ates amyloid pathology in the transgenic AD mouse model.87
ITPR and RYR.68,81,82 Similar to neurons, Ab also triggers cal-
In addition to neurons, loss of BECN1 in microglia, leading to
cium-dependent ER stress in glial cells, which is indicated to
impaired phagocytic clearance, is also a contributing factor for
play an important role in Ab-mediated astrogliosis in vivo.69
exacerbated Ab accumulation.88 The presence of Ab also trig-
Interestingly, although Ab mutation upregulates the expression
gers inflammatory responses in microglia.89 Phagocytosis of
 230 Y. CAI ET AL.
Ab crystals by microglia disrupts the integrity of lysosome and
the release lysosomal proteolytic enzyme CTSB (cathepsin B)
activates NLRP3 (NLR family, pyrin domain containing 3)
inflammasomes. This ultimately culminates in activation of the
IL1B (interleukin 1, b) pathway with subsequent generation of
proinflammatory and neurotoxic factors.89 Reciprocally,
enhancing autophagic activity by genetic deletion of CSTB (cys-
tatin B [stefin B]; an endogenous inhibitor of lysosomal cyste-
ine proteases) or temsirolimus (a drug used for the treatment
of renal cell carcinoma) reduces Ab deposition and exerts pro-
tective effects in both cellular and mouse models of AD
(Fig. 4).90,91 In summary, dysregulated UPR and impaired
autophagy fail to eliminate pathogenic accumulation of abnor-
mal proteins, resulting thereby in increased symptomatology of
AD. Targeting these pathways could thus have therapeutic rele-
vance for the treatment of AD.
In addition to Ab accumulation, there is extensive evidence
on the aggregation of yet another axonal cytosolic protein, the
MAPT that is found hyperphosphorylated as in the brains of
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patients with AD, frontotemporal dementia (FTD), progressive
supranuclear palsy (PSP), corticobasal degeneration, primary
age-related tauopathy (PART) and traumatic brain injury
(TBI).92-95 Mutations in the gene encoding MAPT are most
commonly associated with tauopathies such as FTD, PSP and
corticobasal degeneration, whereas other genetic risk factors
such as mutations in C9orf72 (chromosome 9 open reading
frame 72), GRN (granulin), the gene encoding VCP (valosin
containing protein) and CHMP2B (charged multivesicular
body protein 2B) affecting UPR and autophagy, play an essen-
tial role in frontotemporal lobar degeneration (FTLD) and
AD.96 Whereas the neurodegenerative pathology of tauopathies
has been well recognized, the relevant molecular mechanism(s)
underlying the disease processes remain poorly understood.
Increasing evidence suggests that aggregated MAPT can lead to
ER stress and activation of the UPR as an early event in tauopa-
thies such as AD, FTD and PSP (Fig. 4).80,97 In AD postmortem
brain tissues, activation of UPR mediators such as EIF2AK3,
ERN1 and HSPA5 is observed in the pretangled neurons con-
taining diffusely distributed phosphorylated MAPT, but not in
the neurons with densely aggregated neurofibrillary tangles.98,99
Direct evidence of MAPT-dependent UPR is found in sporadic
tauopathies lacking Ab.80 For example, a report by Nijholt et al.
demonstrated that UPR activation is only observed in the
MAPT subtype of FTLD, but not in other aggregate subtypes of
FTLD.80 Elegant work by Abisambra et al. using MAPT trans-
genic mouse brains has also shown that MAPT increases the
levels of ubiquitinated proteins in the brain and initiates the
activation of the UPR as evidenced by increased levels of phos-
phorylated EIF2AK3. Findings from this group led to the sug-
gestion that the presence of MAPT interferes with ER protein
quality control.93 GSK3B (glycogen synthase kinase 3 b) is an
essential kinase for the phosphorylation of MAPT that plays an
important role in MAPT aggregation.100 Interestingly, the study
by Nijholt et al. has shown that the EIF2AK3 pathway activates
GSK3B through selective removal of inactive GSK3B via the
autophagy-lysosomal pathway.100 Moreover, findings by van
der Harg et al. have also reported that failure to restore the met-
abolic homeostasis resulting in prolonged UPR activation and
MAPT phosphorylation could likely be a contributing factor to
AD pathogenesis. Furthermore, these authors also demon-
strated the role of UPR-mediated MAPT phosphorylation as
part of an adaptive response to metabolic stress, culminating
ultimately into the pathogenesis of AD.101
Hyperphosphorylated MAPT is a target client that is recog-
nized by the chaperone system and is processed initially by the
HSPA/DNAJ (heat shock 70 kDa proteins/DnaJ (Hsp40)
homolog) complex followed by an intermediate complex with
HSP90 (heat shock 90 kDa protein) and STIP1 (stress-induced
phosphoprotein 1).102 Intriguingly, HSP90 regulates the folding
or degradation of its client proteins by forming multicompo-
nent complexes with other chaperones. HSP90 has the ability
to cycle between the different multichaperone complexes, from
a complex favoring the refolding of abnormal proteins in the
presence of ATP to a complex that targets proteins for degrada-
tion (in the presence of ADP).103 Inhibitors for heat shock pro-
teins convert the HSP90 complexes from a catalyst for protein
folding into one that promotes protein degradation.102 These
inhibitors can thus be harnessed to convert the protein folding
form to a protein degradation pathway, thereby allowing for
the removal of abnormal phosphorylated MAPT. In keeping
with this differential function of the chaperone system on toxic-
ity, the extracellular chaperone CLU (clusterin) exhibits para-
doxical roles in the pathology of AD depending on the
concentration of misfolded proteins.104 On the one hand, under
normal conditions CLU can stabilize extracellular misfolded
proteins via its binding to them and subsequently guiding them
to specific cell surface receptors for uptake and degradation.105
Such extracellular chaperones and their receptors form a criti-
cal component of the quality control system to protect the
host against abnormal, aggregated proteins such as Ab.105 On
the other hand, there is also evidence that in the presence of
high levels of misfolded proteins, CLU can actually exacerbate
the pathology.104 Similar to CLU, TTR (transthyretin) can also
regulate aggregated protein quality control by sequestering sol-
uble Ab and thereby preventing the formation of amyloid
fibers.106
ER stress in AD is commonly observed in both Ab and
PSEN1 mutation and MAPT pathology. Interestingly, Ab-
induced calcium-dependent ER stress is suggested to be a con-
served pathway that both neurons and astrocytes share in com-
mon.68,69 Loss of BECN1 impairs autophagy in AD brains and
leads to synaptic injury in neurons, and phagocytic deficits in
microglia, suggesting that autophagy is a conserved pathway
and can affect the functioning of both neurons and glial
cells.87,88 Ab-mediated microglial inflammation further sug-
gests a crucial role of glial cells in modulating AD inflammatory
trajectory.89 However, the UPR and autophagy play a protective
role in neurotoxicity mediated by Ab and PSEN1 mutations83,85
but not in MAPT pathology.100 The phosphorylated EIF2AK3-
dependent autophagy pathway is considered as the major deg-
radation pathway for Ab,86 but is also capable of activating
GSK3B by degrading its inactive forms, leading to MAPT phos-
phorylation and aggregation.100 Thus, intervention in the UPR
and autophagy in AD can be considered as potential therapeu-
tic targets; however, the genetic profiling and pathology of AD
patients should be carefully investigated when designing poten-
tial therapeutic strategies based on the perspective of the UPR
and autophagy.
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Figure 4. ER stress and autophagy in AD. Both mPSEN1 (mutant PSEN1) and Ab induce calcium-dependent ER stress, resulting in astrogliosis and neuronal injury. Loss of
BECN1 not only contributes to neuronal damage but also debilitates the phagocytic function and induces inflammatory responses in microglia. Interestingly, mPSEN1 ren-
ders neurons vulnerable to ER stress by suppressing major UPR mediators while MAPT protein enhances its phosphorylation through activation of UPR mediators, espe-
cially EIF2AK3. The EIF2AK3-dependent autophagy pathway is crucial for degradation of Ab, and autophagic activities can be also enhanced by genetic deletion of CSTB/
cystatin B or treatment with temsirolimus. However, autophagy mediated by EIF2AK3 signaling also activates GSK3B by removing its inactive form resulting in subsequent
phosphorylation and aggregation of MAPT protein. Moreover, ATPase inhibitors for HSPA/DNAJ complexes and HSP90 multi-component complexes facilitate the triage of
MAPT toward the ERAD pathway. CLU and TTR are able to bind to aggregated proteins to prevent their aggregation.

Prion diseases noninfected brain, and as a protease-resistant form of prion

protein PRNPSC in the prion diseased brain.110 In prion dis-
Prion diseases, also known as transmissible fatal neurodegener-
eases, PRNPC is converted into PRNPSC that is rich in b-sheet
ative diseases, are characterized by neuronal loss, synaptoden-
and prone to intracellular accumulation, resulting in ER
dritic degeneration, spongiosis, gliosis and deposition of
stress.110 The conversion also depletes PRNPC in neurons and
insoluble PRNP (prion protein) aggregates in the brain.107-109
stimulates synthesis of PRNPC for further cycles of conversion,
PRNP exists as a native form of prion protein PRNPC in the
thereby exacerbating ER stress.109 A similar template for
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Figure 5. ER stress and autophagy in prion diseases. ER stress induced by disruption of intracellular calcium homeostasis is also observed in prion diseases. Aggregation of
PRNP upregulates ER chaperones and activates EIF2AK3-EIF2S1 signaling, resulting in synaptic failure and activation of a caspase cascade, which can be rescued by the
EIF2AK3 inhibitor GSK2606414 but not the PPP1R15A inhibitor salubrinal. Overexpression of UPR mediators such as ATF6, ATF4 and XBP1 reduces PRNP aggregation in
vitro, but it is not fully extrapolated in XBP1 conditional knockout mice. RTN3 activated by ER stress restrains autophagy by prohibiting dissociation of BCL2 and BECN1.
Autophagic activities can be enhanced by overexpression of SIRT1 and autophagic inducers, and can be inhibited by either genetic silencing of ATG5 or in the presence
of the autophagic inhibitor 3-MA.

conformational change is also observed in other prion-like dis-
ease-specific proteins including MAPT, Ab and SNCA.111-113
Accumulating evidence suggests active ER stress responses
in prion diseases both in vitro and in vivo (Fig. 5).114-117
Transcriptional analysis of brainstem tissues from 100 con-
firmed cases of prion diseases in cattle found increased
expression of ER chaperones, ERAD components, regulators
of ER calcium storage and mediators of ER stress-induced
apoptosis.118 Upregulation of ER chaperones HSPA5, PDIA3
(protein disulfide isomerase family A, member 3), and
HSP90B1 (heat shock protein 90 kDa b [Grp94], member 1)
has been reported in N2a neuroblastoma cells infected with
scrapie in vitro and scrapie rodents models in vivo.114-117
Prion proteins also increase the release of ER calcium into
 AUTOPHAGY 233

cytosol, induce inhibition of global protein synthesis, and Parkinson disease

cause dysregulation of autophagy. PRNP can induce ER
PD is the second most common neurodegenerative disorder
stress-dependent apoptosis through disruption of calcium
afflicting the elderly and is usually characterized by hypokine-
homeostasis via ITPR and RYR in primary neurons.119
sia, rigidity, and tremor. The extensive degeneration of dopami-
Although overexpression of UPR mediators decreases PRNP
nergic neurons in the substantia nigra pars compacta accounts
aggregation in cell lines in vitro,109,120 the same phenomenon
for the majority of the symptomatology.132,133 The salient path-
cannot be fully extrapolated in neurons in XBP1 conditional
ological features of PD includes accumulation of Lewy bodies,
knockout mice.121,122 Studies by Mallucci and Moreno dem-
intracellular inclusion bodies containing diffuse deposits of
onstrated that in response to accumulation of PRNP, global
misfolded SNCA protein.67 Widely accepted PD models mimic
protein synthesis in prion-diseased mice is inhibited by
apoptosis of dopaminergic neurons through administration of
phosphorylation of EIF2S1 leading to synaptic failure and
PD-related insults such as 6-hydroxydopamine (6-OHDA), 1-
neuronal loss.123 This group further demonstrated that tar-
methyl-4-phenyl-pyridinium (MPPC), 1-methyl-4-phenyl-
geting the upstream ER stress molecule EIF2S1 is able to
1,2,3,6-tetrahydropyridine (MPTP) and rotenone.134,135
reverse cognitive deficits and prevent clinical signs of prion
In PD, phosphorylated forms of the UPR activation marker
disease at the preclinical stage.124 Intriguingly, the ER-resi-
EIF2AK3 colocalize with the SNCA protein in the human sub-
dent protein RTN3 (reticulon 3) that can be activated under
stantia nigra, indicating thereby induction of ER stress and its
ER stress is reported to play an important role in the cyto-
association with the aggregated SNCA.136 Similar findings have
solic PRNPSC aggregation in N2a cells infected with the
been demonstrated in chemically induced experimental models
prion protein fragment PRNP (90–231). RTN3 restrains
of PD. Following exposure to 6-OHDA, there is increased
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autophagic activity by enhancing interaction between BCL2

phosphorylation of EIF2AK3 and ERN1 in neurons, further-
and BECN1, and knockdown of RTN3 not only promotes
more, sympathetic neurons from EIF2AK3 null mice exhibit
the autophagic clearance of PRNPSC, but alleviates the ER
extended sensitivity to 6-OHDA.134 In addition to phosphory-
stress and improves cellular survival.125
lated EIF2AK3, exogenous XBP1 protein also protects dopami-
It has been suggested that insufficient cellular clearance
nergic neuroblastoma SK-N-SH cells from MPPC and
in prion diseases can be partially related to dysregulation of
proteasome inhibitors, and additionally, adenoviral XBP1s sup-
autophagy (Fig. 5).126 Intracellular autophagic vacuoles/
presses MPTP-mediated degeneration of dopaminergic neu-
autophagosomes of different sizes are found located in neu-
rons in mouse models.135 The role of EIF2S1 in the phenotype
ronal perikarya, neurites and synapses in various prion-like
of a-synucleinopathy, however, remains unclear. Although
diseases.29 It has been reported that adenoviral-mediated
phosphorylated EIF2S1 is present in the substantia nigra of PD
SIRT1 (sirtuin 1) overexpression enhances autophagic activ-
individuals,136 it is not found to be activated in the a-synuclein-
ity to protect human neuroblastoma SH-SY5Y cells from
opathy mouse model (A53TaS Tg).137 Interestingly, DDIT3, a
neurotoxicity, mitochondrial injury and an intrinsic apopto-
pro-apoptotic mediator in the final stage of ER stress, is a medi-
sis pathway that are meditated by the prion peptide PRNP
ator of neuronal cell death in the rat substantia nigra induced
(106–126). Knocking down ATG5 abrogates this effect.127
by 6-OHDA but not MPTP. Upregulation of DDIT3 is
The autophagic inducers trehalose and lithium diminish
observed in dopaminergic neuronal cell death mediated by
accumulation of PRNPSC in ScN2a cells (N2a cells persis-
both 6-OHDA and MPTP; however, a null mutation of DDIT3
tently infected with prion strain RML) and this protective
in vivo protects mice from only 6-OHDA-induced apoptosis
effect can be blocked either with 3-methyladenine (3-MA;
(Fig. 6).138 Accumulating evidence thus suggests that UPR reg-
an inhibitor of phosphatidylinositol 3-kinase that inhibits
ulators such as EIF2AK3 and XBP1s play important roles in
cellular autophagy) or by genetically silencing ATG5.128,129
neuroprotection in PD, however, more evidence is needed to
Intraperitoneal injection of the classic autophagic inducer
clarify the roles of EIF2S1 and ERN1 in this process. Although
rapamycin in a transgenic (PRNP-A116V) Gerstmann-
DDIT3 is usually associated with ER stress-associated apopto-
Str€aussler-Scheinker mouse model was also demonstrated to
sis, it appears that the nature of the toxic stimulus determines
decrease PRNPSC accumulation, induce a dose-dependent
whether DDIT3 will induce neuronal apoptosis in PD.
delay in disease onset, alleviate the disease symptoms and
Chaperone-mediated autophagy is crucial for the clearance
extend the life span.130 Using a PRNP-FRET-enabled high-
of soluble SNCA protein in cultured dopaminergic neurons
throughput assay to screen for compounds that decrease
because the SNCA protein contains a pentapeptide sequence
PRNP expression, a recent study on CJD demonstrated that
(95VKKDQ99), and its degradation can be blocked by the lyso-
another autophagic inducer, astemizole (originally used to
somal proteolysis inhibitor ammonium chloride.139 PARK2
treat chronic seasonal allergic rhinitis), prolongs the survival
(parkin RBR E3 ubiquitin protein ligase) is a ubiquitin ligase
time of prion-infected mice, suggesting thereby the possibil-
reported to localize in mitochondria,140 mediate the engulfment
ity of therapeutic use of astemizole in CJD.131
of mitochondria by phagophores, selectively eliminate dysfunc-
Taken together, prion protein induces the release of ER cal-
tional mitochondria141 and rescue the inhibition of mitochon-
cium into cytosol, induces inhibition of global protein synthesis
drial fusion induced by SNCA.142 Dopaminergic
and causes dysregulation of autophagy. Therefore, maintaining
neuroblastoma-derived SH-SY5Y cells transfected with PARK2
the intracellular calcium homeostasis, counteracting the global
are more resistant to cell death induced by tunicamycin
translation repression and enhancing autophagic activities can
(N-glycosylation inhibitor)-mediated ER stress.143 Silencing
be considered as promising therapeutic strategies for combating
EIF2S1 and its downstream target ATF4 reduces PARK2
prion diseases.
 234 Y. CAI ET AL.
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Figure 6. ER stress and autophagy in PD. Phosphorylation of EIF2AK3 can be induced by both SNCA and 6-OHDA. Although phosphorylated EIF2S1 is seen in PD brain but
not in the a-synucleinopathy mouse model, EIF2S1-ATF4 signaling upregulates PARK2. Interaction of PARK2 and BECN1 enhances autophagic clearance of SNCA. More-
over, exogenous XBP1s and XBP1 rescue MPPC/MPTP-mediated dopaminergic neuron degeneration.
expression in mouse primary cortical neurons and disrupts
mitophagic function, leading to increasing neuronal cell
death.144 Interestingly, although PARK2 colocalizes with
BECN1 in human mid-brain, it has decreased interaction with
BECN1 in sporadic PD cases. Furthermore, there was increased
secretion of SNCA from the brain into the blood in PARK2-
deficient mice (Fig. 6).145
Different PD insults all trigger ER stress and activate the
UPR that is suggested to play a neuroprotective role.134,135
PARK2 is a critical neuroprotective molecule bridging the UPR
and autophagy in PD and thus can be considered as a promis-
ing target for therapeutic purposes.144 Although upregulation
of DDIT3 is a common feature in different PD models, DDIT3
mediates neuronal apoptosis in the presence of 6-OHDA but
not in the presence of MPTP,138 an effect that is dependent on
the nature of the PD stimulants. Due to the fact that phosphor-
ylated EIF2S1 is present in human PD brains but not in the
A53TaS transgenic mouse model, more evidence is needed to
clarify the roles of EIF2S1 in this process.136,137
Amyotrophic lateral sclerosis
ALS, often referred to as “Lou Gehrig’s disease,” is a progressive
and fatal adult-onset neurodegenerative disorder with a selec-
tive degeneration and loss of motor neurons, characterized by
muscle weakness, atrophy, spasticity, paralysis and premature
death.146 Whereas most of the ALS cases are sporadic ALS
(sALS), nearly 10% of ALS cases are familial ALS (fALS).146,147
It has been reported that abnormal aggregation of mutant (m)
SOD1 (superoxide dismutase 1, soluble) accounts for about
20% of fALS cases6,148 and 1–7% of sALS cases. Additionally,
mutations in genes, such as those encoding TARDBP (TAR
DNA binding protein), FUS/TLS (FUS RNA binding protein),
and OPTN (optineurin) also are reported to be a causative fac-
tor of ALS.149-151
Various reports suggest that aggregation of mSOD1 results
in prolonged ER stress leading to the loss of motor neurons
through the activation of pro-apoptotic factors such as CASP3,
ATF3, DDIT3 and BH3-only proteins, in the late stages of
SOD1G93A ALS mouse models.152-154 An increase in HSPA5,193
PDI,6 EIF2S1,155 ATF4 and XBP1s156 was also reported in the
post-mortem brains of ALS patients. The chronic ER stress in
fALS patients is likely to be associated with the suppression of
compensatory autophagic clearance of mSOD1. One of the ER-
stress regulators, XBP1, suppresses autophagic clearance of
mSOD1 possibly via inhibition of MTORC1 (Fig. 7).156 Target-
ing inhibition of XBP1 and enhancing autophagic clearance
can be considered a promising therapeutic strategy for clearing
mSOD1 in ALS.
TARDBP, a nuclear RNA-binding protein that plays a criti-
cal role in RNA processing as well as microRNA biogenesis
modulation, continually shuttles between the nucleus and the
cytoplasm.157,158 Under normal conditions, TARDBP is proc-
essed and degraded by both autophagy and the ubiquitin-pro-
teasome systems. When TARDBP is excluded from the nucleus
it forms cytoplasmic aggregates in the brain and spinal cord of
ALS patients.159 Over 30 mutations have been reported in the
TARDBP gene to cause fALS; such mutations endorse the cyto-
plasmic mislocalization and accumulation of TARDBP leading
to cytoplasmic TARDBP toxicity.159 The aggregated TARDBP
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Figure 7. ER stress and autophagy in ALS. Different mutations such as those in SOD1, TARDBP and FUS are all able to induce neuronal apoptosis through activation of
DDIT3. Both TARDBP and FUS can be included in stress granules in the cytoplasm. Phosphorylation of EIF2S1 mediated by TARDBP and mSOD1 (mutant SOD1) facilitates
stress granules formation. Interestingly, either FUS or mSOD1 increases expression of XBP1s but activated XBP1s inhibits autophagic clearance of mSOD1. Moreover,
mOPTN (mutant OPTN) also hampers autophagy by inhibiting fusion of autophagosomes with lysosomes. Enhanced autophagic activity induced by autophagic inducers
leads to clearance of FUS and TARDBP. Interestingly, SQSTM1 plays a crucial role in packaging TARDBP into autophagosomes.

also triggers ER stress both in vitro and in vivo.160,161 The
aggregated TARDBP can also be phosphorylated, ubiquitinated
and degraded by the ubiquitin-proteasome system and autoph-
agy via degradation target proteins such as UBQLN1 (ubiquilin
1) and UBQLN2 (ubiquilin 2), and SQSTM1 (sequestosome 1),
respectively (Fig. 7).162,163 Indeed, various studies demonstrated
a failure of TARDBP clearance in human ALS. Additionally, in
vitro studies demonstrated that the primary mutation of
TARDBP confers resistance to its degradation.164
In addition to TARDBP, another RNA metabolism-associ-
ated protein, FUS, has been identified as a key constituent
within the intracellular protein inclusions in the autopsy tissues
of ALS.164 FUS is predominantly restricted in the nucleus with
little distribution in the cytoplasm of motor neurons; however,
point mutations in the C terminus of FUS cause neuronal cyto-
plasmic FUS-positive inclusions in ALS patients.165 Hence,
FUS reshuffles from the nucleus to the cytoplasm and builds
inclusions in affected motor neurons, where it initiates ER
 236 Y. CAI ET AL.
stress in motor neuron-like cells expressing mutant FUS. The
ER chaperone PDI was observed to colocalize with the mutant
FUS in motor-neuron-like NSC-34 cells as well as in the FUS
inclusions in human ALS lumbar spinal cords, in both sALS
and mutant FUS-linked fALS tissues.161 It was also reported
that the point mutation in FUS diminishes the release of FUS
from accumulating stress granules in cultured neurons leading
to defective autophagy clearance, thereby indicating that activa-
tion of autophagic signaling could be a therapeutic approach
for FUS mutation-associated ALS pathologies (Fig. 7).166
OPTN is an autophagy receptor protein, and mutations in
OPTN have recently been reported as a causative factor for
ALS and glaucoma.167 OPTN is primarily involved in autopha-
gosome maturation by fusion with endosomes and its MYO6/
myosin VI binding partner.168 OPTN is also considered as a
neuroprotective protein, whose accumulation is normally
cleared by the proteasome degradation pathway. The OPTN
E478G mutation, a causative mutation for ALS, is reported to
effectively impair autophagosome recruitment, which further
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confirms the involvement of OPTN mutation and defective
autophagy in the pathology of ALS (Fig. 7).169 Thus, reducing
ER stress and maintaining active autophagy can be considered
as promising therapeutic targets for ALS.
HIV associated-neurocognitive disorders
In the era of combined anti-retrovirus therapy, the prevalence
of HAND is actually on a rise due to a significant increase in
the longevity of the infected patients.170,171 Mechanisms under-
lying HAND pathogenesis, however, remain unclear. Recent
emerging studies provide ample evidence indicating that early
HIV proteins that are not affected by combined anti-retroviral
therapy and that can deregulate the ER stress pathways and
autophagy activity play a crucial role in the development of
HAND.
Tat (transactivator of transcription), one of the key HIV
proteins necessary for virus replication, is capable of activating
ER stress pathways in various types of cells in the brain.168-169
Studies from our lab have demonstrated that Tat-induced apo-
ptosis of human brain microvascular endothelial cells involves
ER stress activation and mitochondrial dysfunction.172 Tat also
upregulates ER stress markers including HSPA5, ATF6 and
phosphorylated EIF2S1 in both cortical neurons and astro-
cytes.173 The fluctuation of cytosolic Ca2C concentration is the
upstream signal for ER activation as evidenced by the depletion
of Ca2C from the ER to the cytoplasm via ITPR and RYR.5,7
Besides Tat, the virus envelope protein gp120 also modulate ER
stress in neurons, which in turn, has been suggested to correlate
with neuronal injury.174 Activation of ER stress contributes to
increased permeability of the blood-brain barrier, and the acti-
vation of microglia and astrocytes, thereby resulting in
enhanced expression of pro-inflammatory factors, and
impairment of brain glutamate homeostasis, leading ultimately
to exacerbated brain inflammation, a hallmark feature of
HAND pathogenesis.172,173,175 In addition to regulating ER
stress activity, HIV proteins also modulate autophagy levels as
demonstrated by autophagy dysfunction in HIV brains.170,176-
178
HIV gp120 and Nef have the ability to affect autophagy lev-
els by targeting various steps of the autophagy pathway.170,179
For example, BECN1 levels are altered in HIV gp120 transgenic
mice,166 whereas Nef blocks the autophagosome maturation
step via interaction with BECN1.179 Through the interaction of
Nef and BECN1, HIV can decrease autophagic influx in
infected cells thereby allowing for its replication.179 HIV Tat
also plays a key role in autophagy during the process of HIV
infection. Tat suppresses autophagy in macrophages180 and
bystander monocytes.181 Noticeably, Tat can also alter neuronal
autophagy levels by blocking autophagosome fusion with the
lysosome by disrupting lysosome membrane integrity, which is
critical for the maintenance of normal lysosomal functioning
(Fig. 8).182,183 Autophagy dysfunction in HIV patients has also
been linked with aging. Intriguingly, young (<50 y) vs. aging
(> 50 y) HIV patients reveal opposite trends in autophagic
activity, with increased autophagy observed in younger com-
pared to older HIV-infected individuals. This phenomenon
suggests that different autophagy-targeting therapeutic strate-
gies will be needed for young versus the old HIV-infected
patients to achieve a beneficial clinical outcome.
Taken together, HIV proteins can affect both ER stress and
autophagy activity to contribute to the development of HAND.
In most cases, ER stress is the upstream signal for autophagy
induction, and autophagy in turn can modulate the tone of ER
stress via a feedback mechanism. In HAND, it is still not clear
whether HIV proteins can sequentially first upregulate the lev-
els of ER stress followed by induction of autophagy or if they
cause the induction of both ER stress and autophagy simulta-
neously, or whether autophagy upregulation precedes ER stress.
Additionally, unlike other neurodegeneration diseases, there is
no clear evidence as to whether targeting the autophagy path-
way can be considered an effective alternative therapeutic
approach to ameliorate the symptoms of HAND. Further inves-
tigation is warranted in this area.
Conclusions and future directions
ER stress in neurodegenerative disorders can be triggered by
either pathogenic accumulation of misfolded proteins such as
Ab in AD,77,78 PRNPSC in prion diseases,110 SNCA in PD92 and
mSOD1 in fALS,152 or depletion of ER calcium stores via the
ITPR and RYR channels in HAND5,7 and AD.68 Intriguingly,
Ab-induced calcium-dependent ER stress is also suggested to
be a conserved pathway that both neurons and astrocytes share
in common that leads to neuronal damage and disruption of
trophic support from astrocytes.68,69 Pathogenic accumulation
of misfolded proteins leading to activation of the UPR, results
in upregulation of mediators such as HSPA5, and the phos-
phorylated forms of EIF2AK3 and EIF2S1, which have been
widely used as indicators of ER stress in various neurodegener-
ative disorders.5,136,155,184 Generic cells such as HEK293 are
powerful tools for studying ER stress. Using a novel methodol-
ogy that activates the transcription factors XBP1 and/or ATF6
orthogonally by small molecules in the same cell, Shoulders
et al. were able to demonstrate remodeling of the ER proteosta-
sis network via the UPR transcriptional programs at the molec-
ular level independent of stress.185 Although most of the
experiments in non-neuronal cells can be extrapolatable to neu-
rons in vivo, exceptions do exist and therefore rodent models
and human brain tissues are indispensable for investigating

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Figure 8. ER stress and autophagy in HAND. Although no direct evidence is found between UPR and autophagy in HAND, it has been suggested that HIV viral proteins
induce ER stress and inhibit autophagic clearance. Both gp120 and Tat induce calcium-dependent ER stress, and Tat increases expression of major UPR mediators such as
HSPA5, ATF6, phosphorylated EIF2AK3 and EIF2S1. Viral proteins such as Nef and gp120 hamper autophagosome formation initiated by BECN1 while Tat hinders the
fusion of lysosomes with autophagosomes. BBB, blood-brain barrier.
neurodegenerative disorders. For instance, overexpression of
UPR mediators such as ATF6, ATF4 and XBP1 decrease PRNP
aggregation in cell lines in vitro,109,120 but the same phenome-
non cannot be fully extrapolated to neurons in XBP1 condi-
tional knockout mice.121,122 Under most circumstances,
upregulated expression of UPR mediators is a pathway for pro-
tecting neurons against ER stress; however, it must be cau-
tioned that not all upregulated UPR mediators confer
neuroprotection. For example, in fALS upregulation of XBP1
mRNA decreases MAP1LC3B-II, thereby inhibiting autophagic
clearance of mSOD1.156 In prion diseases, the EIF2S1-depen-
dent prolonged global suppression of protein translation leads
to synaptic failure and neuronal loss.123,186-191 In tauopathies,
activation of GSK3B by the EIF2AK3 pathway results in phos-
phorylation of MAPT in the lysosome.86,100 These UPR media-
tors can thus be envisioned as potential therapeutic targets.
Depending on the nature of the toxic stimuli and the signaling
pathway, both upregulation and downregulation of UPR medi-
ators can direct the course of disease pathogenesis. For
instance, in AD, Ab induces expression of the ER chaperone
HSPA5 to rescue abnormal accumulation of Ab, whereas a
neuronal cell line stably expressing mutant PSEN1 is more vul-
nerable to ER stress stimuli since mutant PSEN1 inhibits the
activity of ER stress sensors HSPA5, ERN1 and ATF6.192,193
Furthermore, maintaining a constant level of ER calcium is
essential for the normal functioning of ER-resident molecular
chaperones. There is also emerging evidence that pharmacolog-
ical inhibitors for ITPR and RYR channels can rescue ER-stress
associated neuronal apoptosis in HAND7 and AD,68 indicating
thereby an important role for loss of the ER calcium store in
the neurodegenerative processes.
Emerging evidence suggests that autophagy serves as an
intrinsic compensatory mechanism for the UPR to regulate
AUTOPHAGY 237
protein homeostasis and clear cell debris and misfolded pro-
teins in neurodegenerative disorders. In the brains of AD
patients, increasing MAP1LC3B levels have been observed in
the phosphorylated-EIF2AK3-positive neurons.86 The ubiqui-
tin ligase PARK2 plays a vital role in the interplay between
ER stress and autophagy. Decreased interaction between
PARK2 and BECN1 is involved in increased secretion of
SNCA from the brain into the blood in the mouse model of
PD.145 Furthermore, dopaminergic neuroblastoma-derived
SH-SY5Y cells transfected with PARK2 are more resistant to
apoptosis mediated by ER stress.143 Some pathogenic pro-
teins such as HIV Tat can escape autophagic clearance via
interference with the endolysosomal pH, inactivation of
endolysosomal enzymes and inhibition of autophagy.194
Interestingly, UPR mediators such as XBP1s can also hamper
autophagic activity by decreasing the expression levels of
MAP1LC3B-II in fALS.156 It is possible that neurons and
non-neuronal cells such as microglia share a common path-
way in autophagy. For instance, loss of the autophagy initia-
tor BECN1 increases intracellular deposition of Ab in
neurons87 and decreases phagocytic clearing, which exacer-
bates Ab in microglial cells.88 Moreover, the dysregulation of
autophagy also contributes to neuroinflammation mediated
by glial cells. With the loss of BECN1, the capacity of han-
dling Ab is diminished in microglia88 and aggregated Ab
damages lysosome, releases the lysosomal protease CTSB and
activates the IL1B pathway, resulting in a microglia-depen-
dent inflammatory response.89 Hence, glial cells play an
indispensable role in mediating neuroinflammation in neuro-
degenerative disorders. With the discovery of lymphatic ves-
sels in the CNS,195 there will be more emerging critical
evidence of neuroinflammation mediated by non-neuronal
cells in modulating the trajectory of neurodegeneration.
 238 Y. CAI ET AL.

MAPK8 mitogen-activated protein kinase 8

Although both in vitro and in vivo approaches have
MAPT/tau microtubule-associated protein tau
advanced our understanding of the molecular pathways under- MBTPS1 membrane-bound transcription factor peptidase,
lying ER stress and autophagy, detailed intrinsic molecular site 1
mechanisms regulating these processes still remain to be eluci- MBTPS2 membrane-bound transcription factor peptidase,
dated. Taken together, available evidence suggests a key role for site 2
MICALL1 MICAL-like 1
dysregulation of these pathways in various neurodegenerative
mOPTN mutant OPTN
disorders. Our knowledge is far from complete, particularly in MPPC 1-methyl-4-phenyl-pyridinium
neurons with regard to cell death/dysfunction. Given the diver- mPSEN1 mutant PSEN1
sity of neuronal populations and neurodegenerative disorders, MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
this represents a challenge. The advent and widespread applica- mSOD1 mutant SOD1
MTORC1 mechanistic target of rapamycin (serine/threonine
tions of new imaging, gene sequencing and mouse genome
kinase) complex 1
engineering tools will contribute significantly to our efforts to NLRP3 NLR family, pyrin domain containing 3
dissect the signaling pathways underlying the UPR and auto- OPTN optineurin
phagy both in development and disease states. PARK2 parkin RBR E3 ubiquitin protein ligase
PARK7 parkinson protein 7
PART primary age-related tauopathy
Abbreviations PD Parkinson disease
PDI protein disulfide isomerase
3-MA 3-methyladenine PDIA3 protein disulfide isomerase family A, member 3
6-OHDA 6-hydroxydopamine PE phosphatidylethanolamine
AD Alzheimer disease PINK1 PTEN induced putative kinase 1
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ALS amyotrophic lateral sclerosis PPP1 protein phosphatase 1

AMPK AMP-activated protein kinase PPP1R15A protein phosphatase 1, regulatory subunit 15A
APP amyloid b (A4) precursor protein PRNP prion protein
ARHGAP26 Rho GTPase activating protein 26 PRNPC native PRNP
ATF3 activating transcription factor 3 PRNPSC protease-resistant PRNP
ATF4 activating transcription factor 4 PSEN1 presenilin 1
ATF6 activating transcription factor 6 PSEN2 presenilin 2
ATG5 autophagy-related 5 PSP progressive supranuclear palsy
ATG12 autophagy-related 12 RTN3 reticulon 3
Ab b-amyloid RYR ryanodine receptor
BBC3 BCL2 binding component 3 sALS sporadic amyotrophic lateral sclerosis
BCL2 B-cell CLL/lymphoma 2 SIRT1 sirtuin 1
BECN1 Beclin 1, autophagy related SNCA/a-synuclein synuclein, a (non A4 component of amyloid precursor)
CALR calreticulin SOD1 superoxide dismutase 1, soluble
CASP3 caspase 3, apoptosis-related cysteine peptidase SQSTM1 sequestosome 1
CJD Creutzfeldt-Jakob disease STIP1 stress-induced phosphoprotein 1
CLU clusterin TARDBP TAR DNA binding protein
CSTB cystatin B (stefin B) Tat HIV-1 transactivator of transcription
CTSB cathepsin B TBI traumatic brain injury
DAPK1 death-associated protein kinase 1 TTR transthyretin
DDIT3 DNA-damage-inducible transcript 3 UBQLN1 ubiquilin 1
DNAJ/HSP40 DnaJ (Hsp40) homolog UBQLN2 ubiquilin 2
EHD1 EH-domain containing 1 ULK1 unc-51 like autophagy activating kinase 1
EIF2AK3 eukaryotic translation initiation factor 2-a kinase 3 UPR unfolded protein response
EIF2S1 eukaryotic translation initiation factor 2, subunit 1 a XBP1 X-box binding protein 1
35kDa XBP1s spliced form of XBP1
ER endoplasmic reticulum
ERAD ER-associated degradation
ERN1 endoplasmic reticulum to nucleus signaling 1 Disclosure of potential conflicts of interest
fALS familial amyotrophic lateral sclerosis
FOXO1 forkhead box O1 No potential conflicts of interest were disclosed.
FTD frontotemporal dementia
FTLD frontotemporal lobar degeneration
FUS/TLS FUS RNA binding protein Funding
GSK3B glycogen synthase kinase 3 b
We would like to acknowledge support from National Institutes of Health
HAND HIV-associated neurocognitive disorders
(NIH) grants number DA033150, DA035203 and DA036157 (SB).
HD Huntington disease
HSF1 heat shock transcription factor 1
HSP90 heat shock 90 kDa protein
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