Stressing Endoplasmic Reticulum May Reverse Protein Misfolding in Dementia

Researchers in the United Kingdom have identified a new mechanism that appears to reverse the build-up of “aggregates,” a commonly used term for clusters of misfolded proteins characteristic of diseases like Alzheimer’s and Parkinson’s.

Protein folding is a normal process in the body, and in healthy individuals, cells carry out a form of quality control to ensure that proteins are correctly folded and that misfolded proteins are destroyed. But in neurodegenerative diseases, this system becomes impaired, with potentially devastating consequences. As the global population ages, an increasing number of people are being diagnosed with dementia, making the search for effective drugs ever more urgent. However, progress has been slow, with no medicines yet available that can prevent or remove the build-up of aggregates.

But research out of University of Cambridge’s UK Dementia Research Institute reports success reversing the build up of aggregates not by eliminating them, but rather by refolding them.

The team theorized that stressing the endoplasmic reticulum—a membrane structure found in mammalian cells that carries out the synthesis, folding, modification and transport of proteins needed on the surface or outside the cell—could lead to protein misfolding and aggregation.  “Just like when we get stressed by a heavy workload, so, too, cells can get ‘stressed’ if they’re called upon to produce a large amount of proteins,” says Dr. Edward Avezov. “There are many reasons why this might be, for example when they are producing antibodies in response to an infection. We focused on stressing a component of cells known as the endoplasmic reticulum, which is responsible for producing around a third of our proteins—and assumed that this stress might cause misfolding.”

But they found that the opposite was true—stressing the cell actually eliminated the aggregates, not by degrading them or clearing them out, but by unraveling the aggregates, potentially allowing them to refold correctly.  

The main component of this mechanism appears to be one of a class of proteins known as heat shock proteins (HSPs), more of which are made when cells are exposed to temperatures above their normal growth temperature, and in response to stress.

Avezov speculates that this might help explain one of the more unusual observations within the field of dementia research. “There have been some studies recently of people in Scandinavian countries who regularly use saunas, suggesting that they may be at lower risk of developing dementia. One possible explanation for this is that this mild stress triggers a higher activity of HSPs, helping correct tangled proteins.”

“If we can find a way of awakening this mechanism without stressing the cells—which could cause more damage than good—then we might be able to find a way of treating some dementias,” Avezoy adds.

The findings were published recently in Nature Communications.