1. often initiated by transient conformational changes of

Topic: HealthDisease
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Last updated: June 4, 2019

1. IntroductionProper brain development is essential as it allows for the organism to perform higher brain functions. The differentiation of neural stem cells (NCS) to CNS cells are essential for the development of the brain, altering cellular properties is the function of increased protein synthesis, the quality control of newly synthesized proteins is important to ensure the brain develops properly.

When many misfolded proteins accumulate in the ER, it is known as ER stress. This induces UPR (Unfolded Protein Response) which is the cells attempt to ensure proteostasis through attenuation, refolding and degradation.After Mitosis, neurons will live longer than other types of cells/tissues that do not undergo cell proliferation, UPR Signalling although ensures proteostasis, in excess can cause neurological disorders. Glial cells are especially susceptible to ER stress as their secretory systems are highly advanced.Intrinsically disordered proteins (IDPs) are either completely unstructured or contain large disordered regions in their native state. Some of them substantially tend to form protein self-assemblies such as toxic or non-toxic aggregates and fibrils. IDPs have been postulated to relate to diseases such as Alzheimer’s disease, tauopathy and Parkinson’s disease.

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The aggregation and fibril formation processes are often initiated by transient conformational changes of the IDPs prior to protein self-assembly. The pathological molecular processes of IDPs share multiple common features with those of protein misfolding diseases such as transmissible spongiform encephalopathy and AL-amyloidosis. (229 Words)2. UPR SignallingThere are 3 stress sensors for UPR signalling in mammals: 1.RNA-dependent protein kinase (PKR)-like ER eIF2a kinase (PERK), 2.

Nositol-requiring enzyme 1 (IRE1) 3. Activating transcription factor 6 (ATF6)  PERK is activated when it dimerizes and undergoes autophosphorylation, functioning as a translational inhibitor, after then, it phosphorylates eIF2a, which then attenuates global protein synthesis and reduces protein from building up in the ER by expressing activating transcription factor 4 (ATF4), which triggers a transcriptional program of UPR-related genes,such as those which control redox homeostasis and amino acid metabolism. In addition, ATF4 also promotes CCAAT/enhancer- binding protein homologous protein (CHOP) expression and then induces growth arrest, programmed cell death and the expression of DNA damage 34 (GADD34), which promotes dephosphorylation of elF2a, deactivating PERK. Oligomerization and autophosphorylation activates IRE1. Activated IRE1 generates the  spliced form of the active transcription factor XBP1 (sXBP1) which upregulates ER chaperones and other cytoprotective genes .

Moreover, activated IRE1 promotes mRNA degradation to attenuate the ER protein load through regulated IRE1-dependent decay (RIDD) . Also, activated IRE1 induces the activation of JNK through the complex formation with TRAF2 and ASK1 on the ER membrane, which induces apoptosis. ATF6,  a basic leucine zipper protein (bZIP) contains type II transmembrane transcription factor protein. Under the ER stress, it is transported from the ER membrane to the Golgi apparatus, where it is cleaved by enzymes (S1P) and  (S2P). As a result, the cleaved bodies translocates into the nucleus and promotes the expression of UPR target genes, such as Xbp1, ER chaperones and ERAD components. (255 Words)3. UPR in cells NSCs diffrentiate into CNS cells, neurons, astrocytes and oligodendrocytes.

UPR has critical roles in NSC self-renewal. Loss of H3K79 dimethylation at the Atf4 and Chop promoters causes irreversible Apoptosis NSCs. This that the UPR  leads to NSC differentiation and self-renewal and that ER stress eventually causes programmed cell death. Astrocytes serve to promote neurons for synaptic formation, function, pruning and other homeostatic functions.

Interestingly when compared with neurons,they have a higher resistance to ER stress caused by hypoxia or ischemia, this suggest that astrocytes have seperate UPR signalling pathways. They have the ability to specifically express the ER stress sensor OASIS. Similar to ATF6, OASIS is cleaved in the membrane of the Golgi apparatus by S1P and S2P in response to ER stress. Then, cleaved OASIS fragments induce BiP.

OASIS-transfected C6 glioma cells have been shown to be more resistant to ER stress- induced cell death caused by injury from hypoxia or ischemia. Oligodendrocyte are myelin-forming cell in the CNS. Oligodendrocytes need to synthesize vast amounts of myelin membrane proteins and membrane lipids through the ER to form a mature myelin sheath.

Therefore, oligodendrocytes are suggested to be very sensitive to the disruption of ER homeostasis and secretory pathways. Myelinating cells, including oligodendrocytes in CNS and Schwann cells in peripheral nervous system, have UPR signalling. For instance, although CHOP is involved in the induction of apoptosis in other CNS cells, it does not participate in ER stress-induced apoptosis or cell death in myelinating cells. PERK is dispensable in the normal development of oligodendrocytes.

Studies revealed that three types of UPR receptors and ER chaperones show differential activation and expression during neonatal myelination in the rat cerebellum. These findings suggest that the UPR contributes to the maintenance of proper oligodendrocytes development and myelination in the mammalian brain and that disturbances in UPR signalling under aberrant ER stress inhibit the myelination process, resulting in brain malformation and disorders. However, the precise molecular mechanism of oligodendrocyte development relative to the UPR remains elusive. Therefore, understanding the physiological and potential roles of the UPR in oligodendrocytes in the application of treatments for demyelinating diseases such as MS requires further investigation.


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