Summary: Researchers describe a newly discovered cellular mechanism that can reverse the accumulation of protein aggregates by refolding them rather than degrading them.
Source: University of Cambridge
Small amounts of stress can sometimes be beneficial. New research shows that, in cells, a specific stress response may help undo harmful protein tangles linked to dementia by refolding aggregated proteins instead of simply removing them.
Neurodegenerative conditions such as Alzheimer’s and Parkinson’s diseases are marked by the accumulation of misfolded proteins. In Alzheimer’s, for example, proteins like amyloid and tau can misassemble into aggregates that damage neurons and compromise brain function.
Protein folding is an essential biological process. Healthy cells maintain protein quality by ensuring newly made proteins fold correctly and by clearing those that misfold. When this quality-control machinery fails, misfolded proteins can accumulate and form toxic aggregates, contributing to neurodegenerative disease.
As populations age globally, dementia diagnoses are rising, intensifying the need for therapies that prevent or reverse protein aggregation. To date, no approved drugs reliably prevent or remove these aggregates in patients, making new mechanistic insights especially important.
In a paper published in Nature Communications, a team led by researchers at the UK Dementia Research Institute, University of Cambridge, reports a previously unknown mechanism in the endoplasmic reticulum (ER) that appears capable of reversing protein aggregation by refolding aggregated proteins rather than destroying them.
“Just as people can feel stressed by a heavy workload, cells can experience stress when called on to produce large amounts of protein,” said Dr Edward Avezov of the UK Dementia Research Institute. He noted that cells sometimes produce large protein quantities—for example, when generating antibodies during an immune response—and that the ER, which makes roughly a third of cellular proteins, is central to this process.
The ER is a membrane-bound organelle responsible for synthesizing, folding, modifying and transporting many proteins destined for the cell surface or secretion. The researchers initially predicted that stressing the ER would reduce its folding capacity and increase aggregation. Instead, their experiments revealed an unexpected outcome.
Under induced ER stress, aggregates did not increase. Rather, many aggregates were eliminated within hours. Crucially, this clearance did not result from degradation or removal of the aggregated proteins; the data indicate that aggregates were being unraveled, allowing proteins the opportunity to refold correctly.
“We were astonished to find that stressing the ER triggered a process that disassembled aggregates, potentially giving misfolded proteins a second chance to attain their proper conformation,” said Dr Avezov. He emphasized that harnessing this mechanism without damaging cells through stress could open new therapeutic avenues for some forms of dementia.
The team identified a key player in this disaggregation activity: BiP, a stress-responsive molecular chaperone in the ER that belongs to the broader family of heat shock proteins (HSPs). HSPs are produced at higher levels when cells experience elevated temperatures or other stresses, and they help protect protein integrity by assisting folding and preventing aggregation.
The researchers suggest that increased activity of chaperones like BiP under mild stress could explain observational links between certain lifestyle factors and reduced dementia risk. For example, some epidemiological studies have reported lower dementia incidence among people who frequent saunas; one hypothesis is that mild, repeated thermal stress elevates protective chaperone activity that helps maintain proteome health.
A significant technical advance made this discovery possible: the team developed a live-cell probe that detects protein misfolding with sub-organellar resolution by measuring the fluorescence lifetime of a reporter on a nanosecond timescale. This approach reveals otherwise invisible aggregates inside living cells and allows researchers to follow their dynamics in real time.
“Measuring our probe’s fluorescence lifetime on the nanosecond scale under a laser microscope makes the previously invisible aggregates inside cells clearly visible,” said Professor Eduardo Melo, a leading author from the University of Algarve. This capability was essential for observing how aggregates respond rapidly to ER stress and chaperone activity.
About this neurology research news
Author: Press Office
Source: University of Cambridge
Contact: Press Office – University of Cambridge
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Original Research: Open access. “Stress-induced protein disaggregation in the Endoplasmic Reticulum catalysed by BiP” by Edward Avezov et al., Nature Communications
Abstract
Stress-induced protein disaggregation in the Endoplasmic Reticulum catalysed by BiP
Protein synthesis depends on cellular machinery that helps polypeptides fold into their native conformations and eliminates species prone to aggregation. Protein aggregation underlies many pathologies, including neurodegeneration.
Molecular chaperones antagonize aggregate formation, and cytoplasmic systems can resolve insoluble aggregates; however, whether a similar disaggregation system exists in the ER—where about 30% of the proteome is produced—was previously unknown.
The study shows that the ER in multiple mammalian cell types, including neurons, can resolve protein aggregates when stressed. Using a purpose-built aggregation probe with sub-organellar resolution, the authors observed that steady-state aggregates in the ER are cleared rapidly following pharmacological induction of ER stress.
They demonstrate that this disaggregation activity is catalysed by the stress-responsive ER chaperone BiP, revealing a previously unrecognized, non-redundant aspect of the ER stress response that restores proteostasis.