It’s commonly believed that a little stress is beneficial to your health. Now, scientists have uncovered a novel method that could help avoid the formation of protein tangles, which are typical in dementia.
The accumulation of misfolded proteins is a feature of disorders like Alzheimer’s and Parkinson’s, which are collectively known as neurodegenerative diseases. These proteins form ‘aggregates,’ which can cause irreparable damage to nerve cells in the brain, such as 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 correctly 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 led by scientists from the UK Dementia Research Institute at the University of Cambridge has identified a new mechanism that appears to reverse the build-up of aggregates, rather than eliminating them completely, by ‘refolding’ them, according to a study published today 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 amount of proteins,” explained Dr. Edward Avezov from the UK Dementia Research Institute at the University of Cambridge.
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.
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.”
In mammalian cells, the endoplasmic reticulum (ER) is a membrane structure. It performs a variety of critical tasks, including 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 surprised to discover the opposite 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 unravelling the aggregates, potentially allowing them to refold correctly,” said Dr. Avezov.
“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.”
The key component of this mechanism appears to be a heat shock protein (HSP), which are 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. “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 processes in living cells has been one of the problems that has previously hampered this field of research. The team devised a technology that allows them to detect 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 (one billionth of a second) time frame.
“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.
The UK Dementia Research Institute, which is funded by the Medical Research Council, the Alzheimer’s Society, and Alzheimer’s Research UK, as well as the Portuguese Foundation for Science and Technology, supported the study.
