The role of the unfolded protein response in neurodegeneration

🕒 Approximate reading time: 4 minutes

The Unfolded Protein Response (UPR) has emerged as a vital cellular mechanism that oversees protein synthesis and ensures proper protein folding. While beneficial in maintaining cell health, the UPR can also turn harmful. In this post, we'll delve into the UPR's complexities, its role in the cell, and its relationship with neurodegenerative diseases.

Introduction to the UPR

Every cell in our body is a hub of protein synthesis. These proteins must fold correctly to function optimally. However, sometimes proteins misfold, leading the cell to initiate the UPR:

The UPR's main function is to restore normal cellular function by stopping protein synthesis and activating signals that increase production of molecular chaperones. These chaperones aid in protein folding.

Activation of the UPR

Three primary sensors detect misfolded proteins in the endoplasmic reticulum (ER) and activate the UPR:

  • IRE1 (inositol-requiring enzyme 1)
  • PERK (PKR-like endoplasmic reticulum kinase)
  • ATF6 (activating transcription factor 6)

The UPR in Neurodegeneration

While the UPR is primarily protective, chronic activation can have detrimental effects. Persistent UPR activation can lead to cell death, which is seen in various neurodegenerative diseases. Alzheimer’s, Parkinson’s, and Amyotrophic Lateral Sclerosis (ALS) have all shown evidence of UPR involvement.

Alzheimer’s Disease (AD)

Accumulation of misfolded proteins in AD can activate the UPR. Chronic UPR activation may contribute to the death of neurons in AD.

Parkinson’s Disease (PD)

In PD, there’s evidence that misfolded alpha-synuclein can activate the UPR. Prolonged UPR activation can exacerbate dopaminergic neuron loss, a hallmark of PD.

Therapeutic Potential

Given the UPR's role in neurodegeneration, modulating the UPR might provide therapeutic avenues for neurodegenerative diseases. Drugs that can enhance or temper the UPR might hold promise.

Concluding Thoughts

While the UPR's primary objective is cellular protection, its prolonged activation can be a double-edged sword. As we continue to unravel the intricacies of the UPR, it's crucial to harness this knowledge in therapeutic strategies, aiming for a future with effective treatments for neurodegenerative diseases.