Molecular Mass

Under moderate misfolded protein accumulation, activation of the UPR operates as a feedback mechanism that reinforces protein folding, quality control and protein degradation mechanisms. In addition, UPR signalling enhances macroautophagy, which operates as an efficient mechanism to eliminate large protein aggregates and damaged organelles through the lysosomal pathway.The UPR consists of two central components, a group of specialized stress sensors located at the ER membrane and downstream transcription factors that reprogramme gene expression to enable adaptation to stress or the induction of apoptosis.The UPR is Afatinib mediated by three main signalling branches, including inositolrequiring enzyme. UPR activation induces a rapid and transient translational attenuation that is controlled by PERK through the direct phosphorylation and inhibition of the ubiquitous eukaryotic translation initiation factor. This event efficiently buffers the load of misfolded proteins in the ER by reducing the entrance of newly synthesized proteins into its lumen.In addition to inhibiting global translation, eIF phosphorylation favours the selective translation of the mRNA encoding the transcription factor ATF. ATF controls the expression of various genes involved in apoptosis, autophagy, amino acid SKI II metabolism and antioxidant responses.The most conserved UPR signalling branch, and the on ly one present in yeast, is init iated by IRE. This event excises a nucleotide intron that shifts the coding reading frame of the mRNA.Spliced XBP is a stable and active transcription factor that controls a subset of UPR target genes related to protein folding, ERAD, protein translocation into the ER, lipid synthesis and other processes.ATF is a transcription factor that is anchored to the ER membrane in unstressed cells.ATF can form heterodimers with XBP to control the induction of specific patterns of gene expression.Most studies have linked the induction of downstream PERK signalling events to the induction of cell death.ER stress also activates PERK, which phosphorylates eukaryotic translation initiation factor. This results in the inhibition of protein translation, except that of ATF mRNA.After translocation to the nucleus, ATF induces the expression of ER chaperones, genes related to autophagy, redox control and amino acid metabolism.By contrast, it is important to highlight that in many experimental settings, eIF phosphorylation promotes a strong prosurvival effect. Although less explored, several reports indicate that the IRE pathway also contributes to apoptosis.For example, downstream activation of the JNK and ASK pathway triggers apoptosis under ER stress conditions.In the context of neurodegenerative diseases, this dual aspect of UPR signalling makes it difficult to predict the precise contribution of the pathway to pathological conditions, and elucidating this issue has required extensive functional studies invivo. This need is becoming even more pressing, as increased life expectancy and the concurrent rise in neurodegenerative pathologies become a large health and economic burden.For example, AD is characterized by cognitive alterations, memory loss and behavioural changes.Amy loid plaques and neurof ibrillarytang les are the hallmark lesions in the pathology and both arise from protein misfolding.The plaques are mainly composed of amyloid peptides of amino acids that are produced from the cleavage of the amyloid precursor protein by secretases, whereas neurofibrillary tang les are composed of the aberrantly phosphorylated tau protein.

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