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Related Concept Videos

The Unfolded Protein Response01:37

The Unfolded Protein Response

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The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
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Regulation of the Unfolded Protein Response01:31

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Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
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Amyloid Fibrils03:03

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Amyloid fibrils are aggregates of misfolded proteins.  Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils. 
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Protein Folding Quality Check in the RER01:29

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ER is the primary site for the maturation and folding of soluble and transmembrane secretory proteins. The calnexin cycle is a specific chaperone system that folds and assesses the confirmation of N-glycosylated proteins before they can exit the ER lumen. The primary players of this quality check pipeline are the lectins, ER-resident chaperones, and a glucosyl transferase enzyme. In case the calnexin system in the lumen fails to salvage a misfolded protein, it is transported to the cytoplasm...
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Neural Regulation01:37

Neural Regulation

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Digestion begins with a cephalic phase that prepares the digestive system to receive food. When our brain processes visual or olfactory information about food, it triggers impulses in the cranial nerves innervating the salivary glands and stomach to prepare for food.
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The Proteasome01:13

The Proteasome

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Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
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Related Experiment Video

Updated: Mar 23, 2026

Evaluation of Synapse Density in Hippocampal Rodent Brain Slices
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The UPR and synaptic dysfunction in neurodegeneration.

Oliver J Freeman1, Giovanna R Mallucci1

  • 1Department of Clinical Neurosciences, Clifford Allbutt Building, Cambridge Biomedical Campus, University of Cambridge, Cambridge CB2 0AH, UK.

Brain Research
|March 30, 2016
PubMed
Summary

The unfolded protein response (UPR) pathway, specifically the PERK branch, drives neurodegeneration by reducing protein synthesis. Inhibiting this pathway shows promise for treating memory loss and neurodegenerative diseases.

Keywords:
ER stressIntegrated stress responseNeurodegenerationSynaptic dysfunctionUnfolded protein response

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Area of Science:

  • Neuroscience
  • Cellular Biology
  • Molecular Biology

Background:

  • The unfolded protein response (UPR) is increasingly implicated in neurodegenerative diseases.
  • UPR activation is observed in human brain tissue and animal models of these conditions.

Purpose of the Study:

  • To investigate the role of the PERK branch of the UPR in neurodegenerative disease pathogenesis.
  • To explore the therapeutic potential of targeting eIF2α phosphorylation for neuroprotection and memory enhancement.

Main Methods:

  • Genetic and pharmacological manipulation of the UPR pathway in mouse models.
  • Assessment of protein synthesis rates, learning and memory, synapse number, and function.
  • In vivo testing of a small molecule inhibitor for neuroprotective effects.

Main Results:

  • Over-activation of the PERK-eIF2α pathway directly contributes to neurodegeneration by reducing neuronal protein synthesis.
  • Sustained high levels of phosphorylated eIF2α (eIF2α-P) impair learning, memory, and synaptic integrity.
  • Pharmacological inhibition of this pathway demonstrated significant neuroprotection and prevented neurodegeneration in vivo.

Conclusions:

  • Targeting eIF2α-P-mediated translational failure offers a generic therapeutic strategy for neurodegenerative diseases.
  • This approach rescues synaptic function and neuronal loss, independent of disease-specific proteins.
  • Inhibiting the UPR pathway presents a promising avenue for developing new treatments for dementia and other neurodegenerative disorders.