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University of Cambridge scientists discover that putting stress on cells helps prevent protein tangles seen in dementia

Cambridge scientists were astonished to discover that causing stress to components of our cells could actually help prevent the creation of tangles of proteins seen in dementia.

Neurodegenerative diseases such as Alzheimer’s and Parkinson’s are characterised by the build-up of misfolded proteins.

Dementia patients have difficulty adapting to new situations
Dementia patients have difficulty adapting to new situations

The proteins - such as amyloid and tau in Alzheimer’s - form ‘aggregates’, causing irreversible damage to nerve cells in the brain.

In healthy individuals, cells carry out a form of quality control to ensure that the normal process of protein folding is carried out successfully and misfolded proteins are destroyed. This system is impaired in neurodegenerative disease.

A team of scientists at the UK Dementia Research Institute, at the University of Cambridge, has found a new mechanism that appears to enable the refolding of aggregates.

“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,” said Dr Edward Avezov from the institute. “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 (ER), which is responsible for producing around a third of our proteins – and assumed that this stress might cause misfolding.”

This membrane structure in mammalian cells carries out functions including the synthesis, folding, modification and transport of proteins needed on the surface or outside the cell.

It was thought that stressing the ER might lead to protein misfolding and increasing aggregation by reducing its ability to work properly. But 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.

Pathological phosphorylation (yellow) of tau proteins (red-orange) leads to disintegration of microtubuli in the neuron axon an aggregation of the tau proteins. The transport of synaptic vesicles (orange-violet spheres) is interrupted
Pathological phosphorylation (yellow) of tau proteins (red-orange) leads to disintegration of microtubuli in the neuron axon an aggregation of the tau proteins. The transport of synaptic vesicles (orange-violet spheres) is interrupted

“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.”

It appears that the primary mechanism behind this is a class of proteins known as heat shock proteins (HSPs).

More of these are made when cells are exposed to temperatures above their normal growth temperature and in response to stress.

Dr Avezov suggested: “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 challenge of visualising these processes in live cells has held up progress in the field.

So working with teams from Pennsylvania State University and the University of Algarve, the team developed a technique to allow them to detect protein misfolding in live cells.

It measures light patterns of a glowing chemical over one billionth of a second.

Dementia is characterised by misfolded proteins
Dementia is characterised by misfolded proteins

“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 Prof Eduardo Melo, one of the leading authors, from the University of Algarve, Portugal.

The research, published in Nature Communications, was supported by the UK Dementia Research Institute, which receives its funding from the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK, as well as the Portuguese Foundation for Science and Technology.

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