Bipolar stress, leading to activation of the Unfolded Protein

Bipolar disorder (BD) is a chronicpsychiatric illness characterized by mood swings between maniac and depressivestates that result in cognitive and functional impairments ref 1-3 review. The pathophysiology of thedisease has been related with Endoplasmic reticulum (ER) and mitochondria (ou se põe tudoem maiúsculaout udo em minúscula) ref 4 – review.ER is responsible for protein synthesis, folding and maturation, lipidsynthesis and calcium storageref5.

Theaccumulation of unfolded and misfolded proteins in the ER lumen originates ERstress, leading to activation of the Unfolded Protein Response (UPR). Thisresponse increases the ER protein-folding capacity, reduces protein synthesisand enhances the degradation of misfolded proteins with the aim of re-establishingER homeostasisref 7. The UPR involvesthree specialized sensing proteins: PERK, IRE1? and ATF6ref 6.In resting cells, the ER stress receptors are maintained in an inactive statethrough association with the ER chaperone GRP78/BiP. ref8. Upon ER stress, GRP78 is released from the ER transmembrane signaltransducers leading to the activation of these UPR signalling pathways.

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Afterthe disassociation from the chaperone, PERK dimerizes to promote itsautophosphorylation and activation. Activated PERK phosphorylates theeukaryotic translation-initiation factor 2a (eIF2a) inhibiting general proteintranslation and preventing further protein synthesis. However, phosphorylated eIF2a canselectively increase the translation of mRNAs containing inhibitory upstreamopen reading frames in their 5′ untranslated region, such as activatingtranscription factor 4 (ATF4). This transcription factor promotes cell survivalby inducing genes involved in redox reactions, stress response and proteinsecretion. However Nonetheless, one of the downstream targets of ATF4is a pro-apoptotic protein, CHOP. To promote apoptosis, CHOP activates and inhibin’sinhibits (inhibin é um nome e não um verbo) pro andanti-apoptotic proteins, respectively, and originates oxidative stress andcalcium disruption.  Therefore, dependingon the severity and duration of stress, PERK activation can lead to eithersurvival or cell death. ref 6,7,8 Thedetachment between the GRP78 and the IRE1? leads to (não sei qual a forma maisgramaticalmente correta) an activation process similar to PERK.

Itsactivation (ativação do quê?Do IRE1a, da via?) triggers a kinase activity and an endoribonuclease activitypromoting an atypical splicing of X-box-binding protein (XBP1) mRNA to form atranscriptionally active mRNA, named XBP1s (spliced). The XBP1 translated fromthe spliced mRNA is a transcription factor that regulates the expression ofgenes taking part in protein folding, trafficking and ER-associated proteindegradation processes. It also inhibits CHOP expression, promoting cellsurvival. During ER stress,IRE1 (era suposto serIRE1a?) is switched off earlier than PERK, therefore the protective functionof IRE1 is nolonger present while PERK signalling is still enduring.

Mechanisms to modulatethe duration of IRE1signalling could therefore influence cell fate in terms of death and survival. ref 9 e 10 Dissociation of GRP78 from ATF6allows its translocation to the Golgi where it is cleaved to its active form. Then,it’s(it’s vs it) translocatedto the nucleus to induce expression of genes with an ER stress response elementin their promoter. ref 11 The targets ofATF6 include ER chaperone proteins and the transcription factor XBP1,converging in the IRE1?pathway. Overexpression of ATF6 can induce CHOP mRNA expression as well. Whenthe ER stress is chronic, a typical feature of BD, UPR fails to restore ERhomeostasis leading to autophagy and apoptosis5-8,ref 6 a 11 Mitochondria have pivotal roles in avariety of cellular functions, including energy metabolism, Ca2+ homeostasis,lipid synthesis, and apoptosis.

ref 12 Calcium-regulation of mitochondrialrespiration maintains ATP homeostasis. In conditions of mitochondrial Ca2+overload, a transition pore opens (PTP), releasing cytochrome c and otherpro-apototic factors promoting cellular death by apoptosis.These two organelles can communicatephysically and biochemically with each other thought a contact site calledmitochondria-associated membrane (MAMs). Contact sites are specialized domainswhere two membranes are closely apposed but do not fuse and thus, eachorganelle maintain its identity. ref 13 – papermail.  MAM has a central role in themodulation of several key processes for cell survival, such as ER stress,autophagy, inflammasome signalling and apoptosis.

ER-mitochondria juxtapositionis determinant for cell fate under stressful conditions9-12. Sigma-1 receptor(Sig-1R), a resident chaperone in MAMs, chaperone IRE1? to ensure the correcttransmission of ER stress into the nucleus, regulating UPR. It’s alsoresponsible for the attenuation of oxidative stress and cytokine signalling.Its activation controls a variety of stress-related cellular systems. The dysregulation of communicationbetween the two organelles will affect cell homeostasis, compromising thedownstream events13,14.

Rise of oxidative stress is one of the consequencesof mitochondria impairment, characterized by high reactive oxygen species (ROS)concentrations. This may be linked to inflammatory activation leading to theassembly of the inflammasomes which are formed by microglia andmacrophages15-18 . The assembly can also result from IRE1? and PERK-mediated induction as aresult of UPR, although the mechanism isn’textensively described. NLRP3 inflammasome has been identified as thecharacteristic active inflammasome in BD. This inflammasome is constituted bythree main components: a cytosolic receptor (NLRP3), a caspase-1 and an adaptorprotein. The assembly of this cytosolic complex maturates pro-caspase-1 intocaspase-1 leading to its activation.

Caspase-1 is responsible for thematuration of proinflammatory cytokines IL1? and IL-18, involved in neuroinflammation andneurodegeneration that culminate in inflammatory neuronal death17,18. Sinceinflammasome activation is known to have a regulatory function associated withthe specific ER-mitochondria domains, the miscommunication between organellesand the NLRP3 activation can be correlated.A feature of Bipolar Disorder is themiscommunication between ER and mitochondria. As such, pharmacologicalmanipulation of pathways involved in the process has scientific and clinicalinterest. Tunicamycin and Thapsigargin are drugs that create specific types stressthat have an impact in protein folding in the ER.

Tunicamycin inhibits thefirst step of glycosylation of proteins, which causes extensive proteinmisfolding and activation of the UPR. ref 12Thapsigarin inhibits ER calcium pumps, leading to an increase of cytosolic calcium.The rise of Ca2+ disrupts the homeostasis controlled by themitochondria, influencing the communication between the organelles. ref 14