J Mol Neurosci DOI 10.1007/s12031-015-0633-3

Unfolded Protein Response Pathways in Neurodegenerative Diseases Syed Zahid Ali Shah 1 & Deming Zhao 1 & Sher Hayat Khan 1 & Lifeng Yang 1

Received: 16 March 2015 / Accepted: 28 July 2015 # Springer Science+Business Media New York 2015

Abstract The aggregation of disease-specific misfolded proteins resulting in endoplasmic reticulum stress is associated with early pathological events in many neurodegenerative diseases, and apoptotic signaling is initiated when the stress goes beyond the maximum threshold level of endoplasmic reticulum stress sensors. All eukaryotic cells respond to the accumulation of unfolded proteins in the endoplasmic reticulum (ER) by signaling an adaptive pathway termed as unfolded protein response (UPR). Recently, the focus of research shifted from work on specific proteins as pathogenesis in these neurodegenerative diseases towards a more specific generic pathway known as UPR. ER is a major organelle for protein quality control, and cellular stress disrupts normal functioning of ER. The UPR acts as a protective mechanism during endoplasmic reticulum stress, but persistent long-term stress triggers UPR-mediated apoptotic pathways ultimately leading to cell death. Here in this review, we will briefly summarize the molecular events of endoplasmic reticulum stress-associated UPR signaling pathways and their potential therapeutic role in neurodegenerative diseases.

Keywords Endoplasmic reticulum (ER) . Unfolded protein response (UPR) . Neurodegenerative diseases and apoptotic signaling

* Lifeng Yang [email protected] 1

State Key Laboratories for Agrobiotechnology, Key Lab of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China

Role of Unfolded Protein Response (UPR) in Neurodegenerative Diseases Neurodegenerative diseases are the greatest challenges to global society and scientists in the field of medicine (Table 1). On one hand, good living standards made prolonged human life, but with aging population, risk of neurodegenerative diseases has also increased. Alzheimer’s disease (AD) is one of the major disease in aging population of both developed and underdeveloped world with an estimated 25 million people affected annually (Wimo et al. 2003). All the major neurodegenerative disease including AD, Parkinson’s disease (PD), Huntington’s disease (HD), and prion-related diseases (PrDs) are also known as protein misfolding disorders, and they show similarities in respect of protein aggregation and loss or dysfunctioning of neurons. The aggregation of diseasespecific misfolded proteins occurs in these diseases, such as amyloid beta in AD, alpha synuclein in PD, huntingtin in HD, and prion protein in case of PrDs. So, it is clear that although the aggregated proteins are different in all these neurodegenerative diseases, but there are general similarities observed in these anomalies, such as synaptic dysfunction is the earliest pathology that leads to the loss of dendritic spines and reduced post synaptic density leading to loss of network, and cell death is obvious in all these diseases. Processing of misfolded aggregated proteins in the ER and its relationship with mitochondrial dysfunction has contributed significantly towards the understanding of neurodegenerative diseases (Rubinsztein 2006, Lin and Beal 2006). In addition to several neurodegenerative diseases, some cardiovascular diseases such as atherosclerosis (Vasa-Nicotera 2004, Hetz et al. 2003, 2005, Zhao and Ackerman 2006) and heart failure (Glembotski 2007) have been correlated with unfolded protein response signaling and endoplasmic reticulum stress (Lindholm et al. 2006, Yoshida 2007). Some other diseases where the unfolded

1-Threonine kinase that autophosphorylates itself 2-Splices XBP1 3-Recruitment of TRAF2, ASK1, and JNK complex

1-ER stress sensor 2-Transcription factor 3-Increase expression of genes involved in folding of proteins, degrading proteins, and trafficking of proteins 4-Increases XBP1 mRNA 1-Major cellular chaperone that activates the three arms of UPR i.e., PERK, IRE1, and ATF6 1-ERAD genes increased expression

IRE1

ATF6

Cited from (Doyle et al. 2011)

ATF4

XBP1

1-Increases expression of genes involved in ER stress response, redox reactions, and CHOP, and it is a transcription factor

1-General protein translation inhibition 2-Antioxidant response via NRF2 through ATF4

PERK

GRP78

Role in UPR

Protein name

Reduced signaling at mRNA level via IRE1 signaling in PS1 knock in mouse 1-Role in APP trafficking via alpha secretase complex negative regulation

1-ATF6 activation inhibited via PS1 mutation

1-Phosphorylation of PERK increase in AD 2-PERK signaling inhibition via PS1 mutation 1-IRE1 signaling inhibited via PS1 mutation

Evidence in Alzheimer’s disease

Role of different UPR proteins in neurodegenerative diseases

Table 1

1-Parkin protein mRNA is increased via ATF4

1-Protective effect against death induced by exogenous XBP1

1-IRE1/ASK1/JNK pathway activated in PD paraquat induces phosphorylation of IRE1

Evidence in Parkinson’s disease

1-mSod1 aggregates reduced toxicity through ablation of XBP1

1-ALS patient’s spinal cord showing phosphorylated IRE1 2-Over expression of IRE1 in spinal cord of ALS patients 1-ATF6 translocation to Golgi bodies inhibited via VAPB mutation 2-Increased expression of ATF6 in sporadic ALS patients

1-Increased PERK expression in spinal cord of ALS patients

Evidence in amyotrophic lateral sclerosis disease

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protein response has been reported are cancer, diabetes, and immune system-related disorders (Schroder and Kaufman 2005a, Schnell 2009). Recently, unfolded protein response has emerged as a major pathological event in prion diseases that could have similarities with other neurodegenerative diseases. The role of eukaryotic translation initiator factor 2α (eIF2α) has been controversial, as in PrDs dephosphorylation of eIF2α has been neuroprotective (Moreno et al. 2012), while in salubrinal and tunicamycin-treated cells, the phosphorylated eIF2α was protective (Boyce et al. 2005; Han et al. 2013). The ER stress-related glucose-regulated proteins such as GRP78/BiP, GRP94, and GRP58/ERp57 are released in the most common form of prion disease in human known as Creutzfeldt-Jakob disease (CJD) (Yoo et al. 2002). ER calcium homeostasis is crucial for cell survival mechanisms. Previous experiments on neuroblastoma cell lines (N2A) treated with purified PrPsc from scrapie infected mouse resulted in dysregulated calcium release from ER calcium channels ultimately activating stress-related chaperones GRP78/BiP, GRP94, and GRP58/ERp57 (Torres et al. 2010). ER membrane resident stress protein GRP78/BiP levels are also increased in AD hippocampus (Hoozemans et al. 2005). Inhibition of adaptive signaling of UPR through disruption of activating transcription factor 6 (ATF6) has been recently studied in SH-SY5Y cell model of PD. Alpha synuclein toxicity in ER or cytoplasm disrupts ATF6 signaling and ultimately ATF6 and IRE1-X box-binding protein 1 (XBP1) connection is lost, leading to transcriptional decay (Credle et al. 2015). Similar results regarding the ATF6 relation to IRE1-XBP1 were reported for HD (Fernandez-Fernandez et al. 2011). ER-associated degradation (ERAD) machinery has been extensively studied in many neurodegenerative diseases such as AD, PD, and amyotrophic lateral sclerosis (ALS) (Abisambra et al., 2013; Chung et al. 2013; Cornejo and Hetz, 2013; Nishitoh et al., 2008). ER–Golgi transit plays an important role in relieving ER stress through increased ATF6 signaling (Chung et al. 2013). Currently, all the protein-misfolding diseases have devastating effect on human and animal population due to non-availability of any fruitful therapy on one hand, and on the other hand, the lack of any presymptematic diagnostic facilities further aggravates the condition of affected host. Thus, there is a dire need for novel therapeutic intervention that will work both in the earlier and late phase of protein-misfolding disorders.

Endoplasmic Reticulum and UPR The ER plays a major role in UPR adaptive response signaling, and it resembles a tubule-filled sac where newly synthesized secretory and membrane proteins are transferred for modification and targeting. Proteins are folded in the endoplasmic reticulum prior to glycosylation and disulfide bond

formation (Fewell et al., 2001). The endoplasmic reticulum quality control system is maintained by molecular chaperones, foldases, and lectins (Schroder and Kaufman 2005a). Correct folding of proteins or degradation of improperly folded polypeptides to prevent aggregation of proteins is controlled through endoplasmic reticulum quality control system (ERQCs) (Ellgaard and Helenius 2003). Apart from synthesis and folding of proteins, the endoplasmic reticulum is involved in many other cellular mechanisms such as apoptosis, autophagy, and calcium ion-related peroxisome signaling (Schroder and Kaufman 2005a, Rao and Bredesen 2004, Hetz 2012). To maintain the homeostatic condition within the ER and remove the damaged proteins, autophagy and proteasomal degradation takes place (Benbrook and Long 2012). There are different kinds of degradation processes: the proteasome degrading short-lived (type I) and misfolded/dysfunctional (type II) proteins and autophagy degrading type II and long-lived (type III) proteins (Chen and Yin 2011). It is clear that endoplasmic reticulum stress initiates the autophagic process (Yorimitsu et al. 2006), and the ER by itself serves as major autophagosomal cargo (Bernales et al., 2006). Autophagic vacuoles play a crucial role in the removal of misfolded/ unfolded aggregated proteins. The proteasome inhibition leads to initiation of autophagy during UPR because proteasomal inhibitors induce the accumulation of polyubiquitinated proteins (Kawaguchi et al., 2011). At this point, autophagy prevents cell death by removing accumulated polyubiquitinated proteins (Ding et al., 2007, Ogata et al. 2006). Misfolded/unfolded proteins are accumulated in ER when the ERQCs fails to respond in pathophysiological conditions (Ellgaard and Helenius 2003). In the endoplasmic reticulum stress process, the molecular chaperone failure breaks the maintenance of proteostasis (Merulla et al., 2013), and the ER response involves the inhibition of new protein synthesis followed by induction of transcriptional changes in chaperone genes and also activation of the ERAD system which searches out and removes misfolded proteins by proteasomal degradation (Meusser et al. 2005, Oyadomari et al., 2006). The UPR includes several signaling pathways through which it tries to maintain cellular homeostasis. It is mediated by endoplasmic reticulum transmembrane receptor proteins which are classified as types I and II (Chakrabarti et al. 2011). Inositol-requiring kinase 1(IRE1) and doublestranded RNA-activated protein kinase-like endoplasmic reticulum kinase (PERK) are type I proteins possessing protein kinase activities. ATF6 is a type II transmembrane protein coding a transcription factor (Schroder and Kaufman 2005a). Additionally, glucose-regulated protein 78 (GRP78) also known as immunoglobulin binding protein (BiP), plays a crucial role in the UPR. Unfolded proteins induce the dissociation of GRP78 followed by the activation of PERK, ATF6, and IRE1 pathways (Parmar and Schroder 2012). These receptor

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proteins work in conjunction to balance the unfolded protein/ chaperone system to provide endoplasmic reticulum homeostasis. The abovementioned sensors of stress take part in activating the UPR genes. PERK increases phosphorylation of eIF2α as an immediate response to stress. IRE1 is involved in the activation of ERAD genes via X-box binding protein1(XBP-1) mRNA splicing, and therefore, activation takes place (Ron and Walter 2007). XBP-1 is known as a transcription factor that participates in the expression of genes important to the proper functioning of the immune system and in the cellular stress response (Kaufman et al. 2002). On the other hand, ATF6 cleavage is required for IRE1-dependent splicing of XBP-1 transcription to initiate unfolded protein response (Yamamoto et al., 2007).

Stress-Related Chaperones and UPR Endoplasmic reticulum quality control system is a unique built-in system inside the endoplasmic reticulum to maintain the proper integrity, folding, and function of proteins (Ellgaard et al. 1999; Ellgaard and Helenius 2003). In general, the folding of a typically secreted protein is driven by the hydrophobic effect to minimize the amount of hydrophobic amino acids on the surface of the protein, which also ensures the native conformation with the lowest free energy. Unfolded conformations are characterized by hydrophobic amino acids on the protein surface which leads to abnormal interactions and aggregation with other unfolded proteins. To ensure correct folding of proteins, endoplasmic reticulum and cytosolic chaperones catalyze rate-limiting folding reactions (Fra et al., 1993). For the correct folding of protein, the endoplasmic reticulum harbors several chaperones from which at least three general folding systems can be distinguished, the heat shock protein 70 (HSP70) family of glucose-regulated molecular chaperones 78 (GRP78) (Gething 1999, Kleizen and Braakman 2004), glucose regulating protein 170 (GRP170) and oxygen regulating protein 150 (ORP150) (Saris et al. 1997), the heat shock protein 90 (HSP90) glucose-regulated chaperone 94 (GRP94/HSP94) (Argon and Simen 1999), and the lectin chaperones, calnexin and calreticulin (Williams 2006). In addition, the ER contains many other essential foldases, enzymes, and catalyzing steps that increase their folding rate. For instance, the ER harbors the peptidyl prolyl isomerase (PPI) that catalyzes the cis–trans isomerization of peptidyl proline bonds and the protein disulfide isomerase (PDI) catalyzing the formation of disulfide bonds. Furthermore, the endoplasmic reticulum is the site of N-linked glycosylation system, which is part of the protein folding and maturation process in the endoplasmic reticulum (Kim et al., 2008). The selected proteins for secretion and membranes which are destined to be translated are censored by a well-organized signaling procedure from ribosome to the ER. Ribosomes

bind to the rough endoplasmic reticulum (rER) through the signal recognition particle (SRP), and the growing peptide is inserted into the lumen of ER via ER membrane protein translocator (aka translocon), the Sec61p translocation channel. GRP78 (glucose-regulated protein 78 kDa) which is also known as BiP (Immunoglobulin binding protein) acts as a thermostat and regulates the ER homeostasis and is involved in the binding of the newly synthesized proteins and removing of misfolded proteins out of the endoplasmic reticulum to the proteasomes, a process called ERAD. BiP has an unfolded protein binding site through which it helps in folding of proteins and prevents aggregation (Kleizen and Braakman 2004). BiP has a wide substrate spectrum due to low affinity to short hydrophobic peptides. Characteristic of HSP70 class chaperones is a conserved N-terminal ATPase domain and a Cterminal substrate-binding domain. Binding and release of substrates from BiP is catalyzed by ATP–ADP cycling. ATP hydrolysis releases the peptides from BiP in a reaction stimulated by DnaJ-like co-chaperones, such as MTJ1 (murine transmembrane protein) (Chevalier-Larsen and Holzbaur 2006). GrpE co-chaperone Sil1p/BAP (BiP-associated protein), a nucleotide exchange factor, catalyzes the ADP–ATP exchange reaction (Chung et al. 2000). ATP-deficient cells are unable to fold protein, and as a result, cells are in limited capacity to import ATP which leads to ER stress during active secretion (Schroder 2008). Upregulation of BiP is a marker of accumulation of unfolded proteins in the endoplasmic reticulum. Functionally, BiP is also regulated at the level of oligomerization. In oligomeric state, BiP is phosphorylated and ADP-ribosylated, while the monomeric and unmodified form of BiP alone is able to associate with unfolded proteins (Freiden et al. 1992). The monomeric form of BiP is the result of unfolded protein response during which the storage pool of oiligomeric BiP turns to monomeric pool (Freiden et al. 1992, Laitusis et al. 1999). The GRP94 chaperone presents the unfolded peptides to holdases and chaperones that bind partially folded peptides such as PDIs and PPIs. Unfavorable folding conditions, such as increased ATP consumption by HSP70 foldases induce the buffering activity of holdases (Winter and Jakob 2004). The ER-translated proteins are glycosylated, and its glycosylation continues in the Golgi apparatus as posttranslational modification. The lectin chaperones come into action by assisting in correct glycosylation reactions and retain the unfolded Nlinked glycoproteins in the ER. The folding protein is de and reglycosylated a few cycles in reactions catalyzed by αglycosidase and uridine diphosphate (UDP)glucose:glycoprotein glycosyl transferase (UGGT), respectively. During glycosylation cycle, monoglycosylated proteins are retained by lactins calnexin and calreticulin in the endoplasmic reticulum. The reglycosylation reaction starts with UGGT acting on unfolded protein reaction, and improperly folded proteins are finally transferred via calnexin to the

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Mn11p/Htm1p/EDEM (endoplasmic reticulum degradationenhancing α-mannosidase-like protein) that induces retrotranslocation to the cytosol for proteasomal degradation (Molinari et al. 2003). The PDI known as ERp58 holds both oxidoreductase and chaperone activities and mediates redox-dependent folding and unfolding of proteins in the endoplasmic reticulum (Hebert and Molinari 2007). Via the activation of PDI, disulfide bond formation is catalyzed, and therefore, it participates in ERAD (Molinari et al., 2002).

Endoplasmic Reticulum Stress-Associated Triad of UPR PERK Pathway There are several reports of PERK pathway activation in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and prion diseases (Hoozemans et al. 2009, Moreno et al. 2012, Bellucci et al. 2011). PERK is a transmembrane sensor protein with luminal and cytosolic kinase domains, found as a monomer at the ER membrane bound by GRP78 chaperone via ATPase binding region in the stress-free conditions. Accumulation of unfolded proteins within the lumen of ER results in the breakdown of PERK/GRP78 complex that allows shuffle of PERK from monomerized to dimerized form and subsequent transautophosphorylation (Sood et al. 2000). The PERK and IRE1 have a similar activation mechanism and a possible reason for that could be similarity in domains. The most acknowledged function of activated PERK is transient phosphorylation of the subunit of the eiF2α that inhibits translation of most mRNAs (Sood et al. 2000). Phosphorylation of eiF2α inhibits the exchange of guanosine diphosphate (GDP) to guanosine triphosphate (GTP) by the guanine nucleotide exchange factor (GEF) eIF2β that is necessary for the activity of eiF2α. This results in sequestration of an important translation initiation intermediate, methionyl tRNA (tRNAMet) (Bertolotti et al. 2000). This decline in translation is followed by an induced ERAD process for the degradation of accumulated proteins. However, the translation of some specific proteins, including internal ribosomal entry sites such as activating transcription factor 4 (ATF4), glucose-regulated protein 94 (GRP94), and glucose-regulated protein 78 (GRP78) increases via PERK activation (Harding et al. 2000, Scheuner et al. 2001). ATF4 induces both pro-survival (early) and pro-apoptotic (late) gene expression. ATF4 is the most studied protein in this family; it is a basic leucine zipper (bZIP) transcription factor involved in the expression of survival genes such as GRP78 and GRP94 (Harding et al. 2000). In addition to this activity, ATF4 upregulates growth arrest and DNA damage-inducible protein 34 (GADD34), and therefore, translational recovery of eIF2α

by dephosphorylation occurs (Novoa et al. 2001). PERK signaling is activated by nuclear respiratory factor 2 (NRF2), which is an antioxidant-response gene involved in the survival process of ER stress (Cullinan and Diehl 2006). PERK induces the dissociation of the NRF2 complex with kelch-like ECH-associated protein 1 (Keap1) and results in the activation of this transcription factor through the antioxidant-response element (Nguyen et al., 2000). ER stress has been shown to induce reactive oxygen species formation in PERK negative cells, which also confirmed the involvement of NRF2 in endoplasmic reticulum stress sensitivity (Cullinan et al. 2003). PERK is regulated via several pathways to control its central role in translation. First, cellular inhibitory protein 58 (P58IPK) can inhibit the cytosolic domain of PERK (Van et al. 2003). P58IPK induction is a signal for the end of UPR adaptive response and the initiation of the apoptosis response to endoplasmic reticulum stress (Szegezdi et al., 2006). Second, PERK activity is regulated via eIF2α dephosphorylation induced by C/EBP homologous protein 10 (CHOP) and therefore activating GADD34. This pathway is a feedback mechanism of PERK via CHOP activation (Novoa et al. 2001). IRE1α Pathway Ire1α is the most studied of all endoplasmic reticulum stress sensors, and like other stress sensors, this endoplasmic reticulum-bound sensor also has two major domains, endoplasmic reticulum luminal domain and cytosolic kinase and RNase domain (Tirasophon et al. 1998, Wang et al. 1998). Homo-oligomerization of Ire1α takes place when GRP78 is dissociated or by the direct binding of unfolded proteins during UPR (Hetz and Glimcher 2009). As a consequence to all these processes, cytosolic kinase domains are transphosphorylated, and subsequently, RNase are activated. The excision of a 26-nucleotide fragment from XBP1 mRNA is a result of endoribonuclease activity of Ire1α (Fig. 1). This modification of XBP1 yields a spliced form of XBP1 mRNA (XBP1s) which is translated into an active transcription factor (Yoshida et al. 2001, Calfon et al. 2002). The binding of translated XBP1 to certain promoters which contain the endoplasmic reticulum stress element (ERSE) consensus sequences results in transcription of GRP78 and other ER resident chaperones (Yoshida et al. 2001) (Fig. 1). Apart from this, XBP1 also binds with another cis-acting element known as unfolded protein response element (UPRE) which is found predominantly in ERAD (Yamamoto et al. 2004). Alternatively, phosphorylation of Ire1α takes place which acts as a platform for activation of tumor necrosis factor (TNF)-receptor associated factor 2 (TRAF2), and the inhibitor of kappa B (IκB), apoptosis signal regulating kinase 1 (ASK1), and I kappa b kinase (IKK). All the mentioned events lead to the activation of certain kinases such as Jun N-terminal kinase (JNK),

J Mol Neurosci Fig. 1 ER stress pathways. See text for details. ATF4/6 activating transcription factor 4/6, BiP immunoglobulin binding protein, CHOP C/EBP homologous protein, GADD34 growth arrest and DNA damage-inducible protein, ROS reactive oxygen species, ERAD ER associated degradation, JNK c-Jun Nterminal kinase, IF2α eukaryotic translational initiation factor 2α, IRE1 inositol-requiring kinase 1, PERK PKR-like endoplasmic reticulum kinase, S1P/S2P site 1/2 protease, XBP1 X-box binding protein 1

BIP

Misfolded proteins in ER

BIP

BIP

BIP

BIP BIP

P E R K

P

A T F 6

P

eIF2α

BIP

BIP

BIP P E R K

BIP

P

I R E 1 α

XBP1u

eIF2α

P T R A N S L A T I O N

I R E 1 P α

R I D D

JNK

Splicing into S1P & S2P R N A

Golgi apparatus GADD34

ATF4

XBP1s

NUCLEUS C H O P

TRANSLATION

D E C A Y

X B P

A T F 4

AUTOPHAGY

ROS PRODUCTION

extracellular signal-regulated kinase (ERK), and mitogenactivated protein kinases 38 (MAPK p38) (Hetz and Glimcher 2009). As a consequence, caspase-12 is released from ER membranes which link the ER stress to JNK pathway, and subsequent initiation of death signals takes place (Yoneda et al. 2001). ATF6 Pathway Recent studies on PD and HD show a comprehensive relationship between ATF6 and IRE1-XBP1 pathways in response to ER stress-related chaperone activation (Fernandez-Fernandez et al. 2011, Credle et al. 2015). In resting condition, ATF6 is localized in the ER and bound to the chaperone GRP78 (Shen et al. 2002) (Fig. 1). This interaction of ATF6 and GRP78

1

SURVIVAL

INCRESED ER PTOTEIN FOLDING CAPACITY AND ERAD

APOPTOSIS

masks two Golgi bodies localized signals which get exposed when unfolded proteins are accumulated and GRP78 is sequestrated. The cleavage of Golgi resident site-1 and site-2 proteases (S1P and S2P) with ATF6 (p90ATF6) results in the generation of a cytoplasmic basic leucine zipper (bZIP) transcription factor N-ATF6 (p50ATF6) (Shen et al. 2002) (Fig. 1). When N-ATF6 is translocated to the nucleus, transcription of genes containing the ERSE-I, II, or cAMP response elements (CRE) consensus sequence takes place. There are a few upregulated target genes by ATF6 such as GRP78, XBP1, and CHOP under stressed conditions (Haze et al. 1999, Yoshida et al. 2001). In addition, ER calcium and glycoprotein-binding chaperon calreticulin is bound to ATF6 (Hong et al. 2004b). Under normal circumstances, ATF6 is normally found in a glycosylated form, and underglycosylated

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forms of ATF6 are observed under UPR conditions, for instance, calcium depleted ER under stress conditions (Hong et al. 2004b). Furthermore, ATF6 activation takes place after stress inducer tunicamycin (Tu) chemical inhibition of N-glycosylation (Haze et al. 1999). Other ER stress inducers such as, thapsigargin (Tg) causes ER calcium depletion via inhibition of the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) pumps and ATF6 cleavage and underglycosylation occurs (Hong et al. 2004b; Haze et al. 1999). In addition, thapsigargin and tunicamycin induce proteasomal degradation of ATF6 independent from cleaving S1P/S2P (Hong et al. 2004a). Inhibition of proteasomal activity is a target to reduce the levels of ATF6 in ER stress conditions, but it can stabilize ATF6 levels under resting conditions (Hong et al. 2004a). ATF6 rapid turnover by UPR-dependent mechanism is thought to have evolved to keep ATF6 in guard from accidental triggering of the unfolded protein response.

Concluding Remarks The UPR has emerged as a major target in all neurodegenerative diseases, and activated UPR has been noticed in many post mortem patients’ brain suffering from different neurodegenerative diseases as well as in animal models of these diseases. ER is a major organelle for correct processing of proteins to maintain cellular homeostasis. Neuronal function and survival is exclusively dependent upon proper functioning of neuronal networks. The accumulation of unfolded proteins in the ER is the most important feature of many neurodegenerative diseases, which results in hampered neuronal transport mechanisms and synaptic malfunctions. The field of UPR is wide open to further molecular and genetic level research specifically in neurodegenerative diseases as there is some very conflicting evidence about modulatory mechanisms such as whether eIF2a-P should be activated or inhibited in aiming to protect neurons. No study has yet to combine both inhibitory and activating drugs to control the beneficial (ATF6) and pro-apoptotic (PERK) branches of the UPR. Complex integration exists among the branches of the UPR. It is therefore intriguing to hypothesize that therapeutic control of more than one branch of the UPR would provide the most beneficial outcomes in halting progression of neurological diseases. The majority of previous UPR work is done on non neuronal cells, so a line of study specifically targeting UPR pathways can be a good neuroprotective therapeutic choice to avoid stress-induced apoptotic signaling between major involved organelles such as endoplasmic reticulum and mitochondria in neurodegenerative diseases.

Acknowledgments This work is supported by 948 projects (2014-S9) and the Program for Cheung Kong Scholars and Innovative Research Team in University of China (No. IRT0866).

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