New insight into the toxic proteins that build up in the brains of people with neurodegenerative conditions, like Alzheimer’s and Parkinson’s, could offer treatments for the diseases.
It turns out that it’s the very cells that create these abnormal proteins that also hold the key to breaking them down.
Within a cell is a structure called the endoplasmic reticulum (ER). If the cell is London, then the ER is the Underground: it’s responsible for transporting key workers and the important information they hold around the cell.The ER allows for the movement of proteins and other molecules around the cell, but it can also change them. The folding and modifying of proteins is essential for many bodily processes, and the ER can be kicked into overdrive when it needs to be.
“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, a dementia researcher at the University of Cambridge and one of the authors of the new study. This stress is useful, when our body detects an infection and needs to produce antibodies, for example.
However, Avezov and his team wondered whether the ER’s response to stress could be behind the creation of toxic, misshapen proteins in the brains of dementia patients. These proteins go on to cause irreversible damage to nerve cells – for example, when the protein tau is created in excess in Alzheimer’s disease it can cause tangles between cells in the memory regions of the brain, eventually destroying brain tissue.
Using cells grown in the lab, Avezov subjected the ER to stress, expecting to find a build-up of toxic proteins.
“We were astonished to find that stressing the cell actually eliminated the [build-up] – not by degrading them or clearing them out, but by unravelling the aggregates, potentially allowing them to refold correctly,” said Avezov.
Until now, researchers had believed that once these protein aggregates had formed, it was nearly impossible to clear them. But here, the team had discovered a mechanism capable of repairing the proteins within the cell that created them, said Avezov.
“[Finding out that] stress activates the mechanism opens the doors to finding disease-preventive treatments, particularly by awakening this natural cell's ability,” said Avezov.
Stressing the brain cells of dementia patients is not a viable treatment, however, as stressed cells could cause further damage to the tissues that surround them. Still, these insights into the molecular machine that unravels the proteins could also lead to the identification of drugs already used in medicine that might have the same effect.
One particular compound that aids the unfolding of the toxic aggregates is a protein called HSP that responds to increases in heat. This understanding, Avezov said, may answer an unexplained finding in the field: that people in Scandinavian countries who regularly use saunas 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.”
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