Stress helps remove the formation of toxic proteins in dementia

It is commonly believed that a little stress is beneficial for health. Recently, researchers have discovered a novel method that could help avoid the formation of protein tangles, which are typical in dementia.

Stress helps remove the formation of toxic proteins in dementia

Image Credit: University of Cambridge

Misfolded proteins accumulate in disorders like Alzheimer’s and Parkinson’s, which are commonly described as neurodegenerative diseases. These proteins form “aggregates,” which can trigger irreparable damage to nerve cells in the brain, like amyloid and tau in Alzheimer’s disease.

Protein folding is a natural bodily activity, and in healthy people, cells perform quality control to ensure that proteins are folded accurately and that misfolded proteins are eliminated. This system, however, is compromised in neurodegenerative illnesses, with potentially fatal effects.

As the world’s population ages, more people are being diagnosed with dementia, making the quest for effective treatments even more important. However, progress has been gradual, with no treatments currently available to prevent or eliminate aggregate build-up.

A team headed by researchers from the UK Dementia Research Institute at the University of Cambridge has identified a novel method that seems to reverse the build-up of aggregates, rather than eliminating them, by “refolding” them. The study was published in Nature Communications.

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 number of proteins.”

Dr Edward Avezov, UK Dementia Research Institute, University of Cambridge

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,” Dr Avezov added.

In mammalian cells, the endoplasmic reticulum (ER) is a membrane structure. It performs a variety of critical tasks, such as protein synthesis, folding, modification, and transport on the cell surface and outside the cell.

Stressing the ER, according to Dr Avezov and colleagues, may cause protein misfolding and aggregation by reducing its ability to function properly, resulting in higher aggregation.

They were taken aback when they discovered the contrary was true.

We were astonished to find that 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.”

Dr Edward Avezov, UK Dementia Research Institute, University of Cambridge

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,” Dr Avezov said.

The key component of this process appears to be a heat shock protein (HSP), which is produced in greater numbers when cells are exposed to temperatures higher than their usual development temperature and in reaction to stress.

Dr Avezov believes that this could explain one of the more odd findings in dementia research.

He further states, “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.”

The difficulty to visualize these mechanisms in living cells has been one of the problems that have previously hampered this field of research. The team devised a technology that enables them to identify protein misfolding in live cells, in collaboration with scientists from Pennsylvania State University and the University of Algarve. It works by monitoring the light patterns of a blazing chemical on a nanosecond scale (one billionth of a second).

It’s fascinating how measuring our probe’s fluorescence lifetime on the nanoseconds scale under a laser-powered microscope makes the otherwise invisible aggregates inside the cell obvious,” said Professor Eduardo Melo, one of the leading authors, from the University of Algarve, Portugal.

Journal reference:

Melo, E. P., et al. (2022) Stress-induced protein disaggregation in the endoplasmic reticulum catalyzed by BiP. Nature Communications.


The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of AZoLifeSciences.
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