Summary: A study reveals a new mechanism that appears to reverse the buildup of protein aggregates by folding them up rather than suppressing them.
Source: University of Cambridge
It is often said that a little stress can be good. Now scientists have shown that the same may be true for cells, uncovering a newly discovered mechanism that may help prevent the buildup of protein tangles commonly seen in dementia.
A hallmark of diseases such as Alzheimer’s disease and Parkinson’s disease, known collectively as neurodegenerative diseases, is the accumulation of misfolded proteins. These proteins, such as amyloid and tau in Alzheimer’s disease, form “aggregates” that can cause irreversible damage to nerve cells in the brain.
Protein folding is a normal process in the body, and in healthy individuals cells perform a form of quality control to ensure that proteins are folded correctly and that misfolded proteins are destroyed. But in neurodegenerative diseases, this system becomes impaired, with potentially devastating consequences.
As the world’s population ages, increasing numbers of people are being diagnosed with dementia, making the search for effective drugs increasingly urgent. However, progress has been slow, with no drugs yet available to prevent or eliminate the buildup of aggregates.
In a study published today in Nature Communicationa 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, not by removing them completely, but rather by “folding” them.
“Just like when we are stressed by a heavy workload, cells can also be ‘stressed’ if they are called upon to produce a large amount of protein,” explained Dr Edward Doveov from the UK Dementia Research Institute at the University of Cambridge. .
“There are many reasons why it could be, for example when they produce antibodies in response to an infection. We focused on stress on a component of cells known as the endoplasmic reticulum, responsible for producing about one-third of our proteins, and hypothesized that this stress could cause misfolding.
The endoplasmic reticulum (ER) is a membrane structure found in mammalian cells. It performs a number of important functions including the synthesis, folding, modification and transport of necessary proteins to the surface or outside of the cell.
Dr.avezov and his colleagues hypothesized that stressing the ER could lead to protein misfolding and aggregation by decreasing its ability to function properly, leading to increased aggregation.
They were surprised to find that the opposite was true.
“We were amazed to find that straining the cell actually removed the aggregates, not by breaking them down or removing them, but by disentangling them, potentially allowing them to fold up properly,” Dr.avezov said.
“If we can find a way to wake up this mechanism without stressing the cells – which could cause more damage than good – then we could find a way to treat certain dementias.”
The main component of this mechanism appears to belong to a class of proteins called heat shock proteins (HSPs), most of which are made when cells are exposed to temperatures above their normal growth temperature and in response to stress.
Dr.avezov thinks this could help explain one of the most unusual observations in the field of dementia research. “There have recently been studies 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 higher activity of HSPs, helping to correct entangled proteins.
One of the factors that has previously hindered this area of research has been the inability to visualize these processes in living cells. Working with teams from Pennsylvania State University and the University of Algarve, the team has developed a technique that allows them to detect protein misfolding in living cells. It relies on measuring the light patterns of a glowing chemical on a scale of nanoseconds, or one billionth of a second.
“It is fascinating how measuring the fluorescence lifetime of our probe at the nanosecond scale under a laser microscope makes otherwise invisible aggregates evident inside the cell,” said the Professor Eduardo Melo, one of the main authors, from the University of Algarve, Portugal.
About this neurology research news
Author: Press office
Source: University of Cambridge
Contact: Press Office – University of Cambridge
Picture: Image is in public domain
Original research: Free access.
“Stress-induced protein disaggregation in the endoplasmic reticulum catalyzed by BiP” by Edwardavezov et al. Nature Communication
Stress-induced protein disaggregation in the endoplasmic reticulum catalyzed by BiP
Protein synthesis is supported by cellular machineries that ensure that polypeptides fold into their native conformation, while eliminating misfolded and aggregation-prone species. Protein aggregation is the basis of pathologies such as neurodegeneration.
The formation of aggregates is thwarted by molecular chaperones, the cytoplasmic machinery resolving insoluble protein aggregates. However, it is unknown whether an analogous disaggregation system exists in the endoplasmic reticulum (ER) where ~30% of the proteome is synthesized.
Here we show that the ER of a variety of mammalian cell types, including neurons, is endowed with the ability to resolve protein aggregates under stress.
Using a specially developed protein aggregation probing system with suborganellar resolution, we observe a steady-state accumulation of aggregates in the ER. Pharmacological induction of ER stress does not increase aggregates, but rather stimulates their clearance within hours.
We show that this disaggregation activity is catalyzed by the stress-responsive ER molecular chaperone – BiP. This work reveals a previously unknown, non-redundant strand of the proteostasis-restoring ER stress response.