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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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In the secretory pathway, vesicles transport proteins from one cellular compartment to another in forward transport to deliver the protein to its correct location. Occasionally, misfolded proteins and incorrect proteins escape their original compartments, and a retrieval pathway is used to return the escaped proteins to their original compartment.
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After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
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Endoplasmic reticulum chaperone genes encode effectors of long-term memory.

Snehajyoti Chatterjee1,2, Ethan Bahl3, Utsav Mukherjee1,2,4

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Nuclear Receptor 4a (Nr4a) proteins regulate endoplasmic reticulum chaperones essential for long-term memory. Enhancing Nr4a1 or Hspa5 improved memory in a dementia model, suggesting new therapeutic avenues for memory loss.

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • Mechanisms of memory loss in Alzheimer's disease and related dementias (ADRD) are not fully understood.
  • Nuclear Receptor 4a (Nr4a) family proteins are known regulators of long-term memory.
  • Endoplasmic reticulum (ER) chaperones play critical roles in protein folding and trafficking.

Purpose of the Study:

  • To investigate the role of Nr4a proteins in regulating ER chaperones involved in memory formation.
  • To explore the therapeutic potential of targeting Nr4a proteins and ER chaperones for ADRD treatment.

Main Methods:

  • Studied the transcriptional regulation of ER-localized chaperones by Nr4a proteins.
  • Utilized a tau-based mouse model of ADRD to assess memory deficits.
  • Investigated the effects of overexpressing Nr4a1 and Hspa5 on memory function in the ADRD model.

Main Results:

  • Nr4a proteins were found to regulate the transcription of genes encoding ER chaperones.
  • These chaperones are crucial for trafficking plasticity-related proteins during synaptic plasticity and memory.
  • Overexpression of Nr4a1 or Hspa5 significantly ameliorated long-term memory deficits in the ADRD mouse model.

Conclusions:

  • Established a novel molecular mechanism linking Nr4a transcription factors, ER chaperones, and long-term memory.
  • Dysregulation of this pathway is implicated in ADRD.
  • Targeting Nr4a proteins and ER chaperones presents a promising therapeutic strategy for cognitive decline in dementia.