Heat shock proteins offer clues to reversing dementia in stressed cells

Researchers investigating the effects of stress on accumulations of toxic brain proteins linked with dementia have discovered a surprisingly counter-intuitive mechanism. A specific cellular stress response involving heat shock proteins has been found to reverse the build-up of these toxic proteins and future research will now look for a way to therapeutically trigger this mechanism.

Many neurodegenerative diseases such as Alzheimer’s and Parkinson’s are characterized by the accumulation of certain proteins in the brain. For a protein to effectively function in a human body it needs to fold into a three-dimensional shape. When proteins “misfold” they are generally destroyed by certain protective mechanisms in the body.

However, in neurodegenerative disease these protective mechanisms are impaired, for one reason or another, and these misfolded proteins begin to aggregate into clumps in the brain. These aggregations are what many researchers suspect are the cause of neurodegeneration associated with dementia.

This new research set out to explore the effects of stress on the mechanisms that influence protein folding. The focus was particularly on a cell membrane structure called the endoplasmic reticulum (ER), which is responsible for synthesizing and folding around one third of the proteins in our body.

The hypothesis was that maybe stress responses increase protein misfolding in the ER. But in a surprising finding, the researchers saw the exact opposite happen – a certain stress response actually unravelled misfolded proteins and degraded pre-existing protein aggregations.

“We were astonished to find that stressing the cell actually eliminated the aggregates – not by degrading them or clearing them out, but by unravelling the aggregates, potentially allowing them to refold correctly,” said Edward Avezov, a University of Cambridge researcher working on the study.

Zooming in on what was actually going on, the researchers discovered this stress-induced reversal of misfolding was driven by a specific molecule in a class of proteins called heat shock proteins (HSPs). Alongside being produced when a cell is exposed to stress, as their name suggests, these proteins are triggered in response to excessive heat exposure.

This particular finding, that a certain HSP may reverse misfolding in proteins associated with dementia, interestingly correlates with some recent observational studies that found men who frequently bathe in saunas may experience lower rates of dementia.

“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,” noted Avezov. “One possible explanation for this is that this mild stress triggers a higher activity of HSPs, helping correct tangled proteins.”

Of course, this kind of preliminary discovery does not mean we should all be rushing out to spend our days sweating in saunas. According to Avezov, exposing our bodies to systemic stressors, including heat, can cause plenty of other harmful effects.

Instead, the promise of this new discovery is in the possibility of finding a targeted way to activate this unique pathway. It is early days, and this new research is still just a mechanism discovered by working with cells in a lab, but if it does translate to animals and humans then it could be a novel way to both prevent and reverse the neurodegeneration that causes some types of cognitive decline.

“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,” said Avezov.

The new study was published in the journal Nature Communications.

Source: University of Cambridge

Researchers investigating the effects of stress on accumulations of toxic brain proteins linked with dementia have discovered a surprisingly counter-intuitive mechanism. A specific cellular stress response involving heat shock proteins has been found to reverse the build-up of these toxic proteins and future research will now look for a way to therapeutically trigger this mechanism.

Many neurodegenerative diseases such as Alzheimer’s and Parkinson’s are characterized by the accumulation of certain proteins in the brain. For a protein to effectively function in a human body it needs to fold into a three-dimensional shape. When proteins “misfold” they are generally destroyed by certain protective mechanisms in the body.

However, in neurodegenerative disease these protective mechanisms are impaired, for one reason or another, and these misfolded proteins begin to aggregate into clumps in the brain. These aggregations are what many researchers suspect are the cause of neurodegeneration associated with dementia.

This new research set out to explore the effects of stress on the mechanisms that influence protein folding. The focus was particularly on a cell membrane structure called the endoplasmic reticulum (ER), which is responsible for synthesizing and folding around one third of the proteins in our body.

The hypothesis was that maybe stress responses increase protein misfolding in the ER. But in a surprising finding, the researchers saw the exact opposite happen – a certain stress response actually unravelled misfolded proteins and degraded pre-existing protein aggregations.

“We were astonished to find that stressing the cell actually eliminated the aggregates – not by degrading them or clearing them out, but by unravelling the aggregates, potentially allowing them to refold correctly,” said Edward Avezov, a University of Cambridge researcher working on the study.

Zooming in on what was actually going on, the researchers discovered this stress-induced reversal of misfolding was driven by a specific molecule in a class of proteins called heat shock proteins (HSPs). Alongside being produced when a cell is exposed to stress, as their name suggests, these proteins are triggered in response to excessive heat exposure.

This particular finding, that a certain HSP may reverse misfolding in proteins associated with dementia, interestingly correlates with some recent observational studies that found men who frequently bathe in saunas may experience lower rates of dementia.

“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,” noted Avezov. “One possible explanation for this is that this mild stress triggers a higher activity of HSPs, helping correct tangled proteins.”

Of course, this kind of preliminary discovery does not mean we should all be rushing out to spend our days sweating in saunas. According to Avezov, exposing our bodies to systemic stressors, including heat, can cause plenty of other harmful effects.

Instead, the promise of this new discovery is in the possibility of finding a targeted way to activate this unique pathway. It is early days, and this new research is still just a mechanism discovered by working with cells in a lab, but if it does translate to animals and humans then it could be a novel way to both prevent and reverse the neurodegeneration that causes some types of cognitive decline.

“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,” said Avezov.

The new study was published in the journal Nature Communications.

Source: University of Cambridge