“Stressed” cells offer clues to eliminate the accumulation of toxic proteins in dementia

Summary: The study reveals a new mechanism that appears to reverse the accumulation of protein aggregates by folding them, rather than removing them.

Source: Cambridge University

It is often said that a little stress can be good for you. Now, scientists have shown that the same can be true for cells, discovering a newly discovered mechanism that could help prevent the accumulation of protein messes that are commonly seen in dementia.

A feature of diseases such as Alzheimer’s and Parkinson’s, collectively known as neurodegenerative diseases, is the accumulation of poorly folded proteins. These proteins, such as amyloid and tau in Alzheimer’s disease, form “aggregates” that can cause irreversible damage to brain nerve cells.

Protein folding is a normal process in the body, and in healthy individuals, cells perform a form of quality control to make sure that the proteins fold properly and that the badly folded proteins are destroyed. But in neurodegenerative diseases, this system is deteriorating, with potentially devastating consequences.

As the world’s population ages, an increasing number of people are being diagnosed with dementia, making the search for effective drugs increasingly urgent. However, progress has been slow, with no drugs available yet that can prevent or eliminate aggregate buildup.

In a study published today in Communications of naturea team led by scientists at the University of Cambridge’s Dementia Research Institute in the United Kingdom has identified a new mechanism that appears to reverse the accumulation of aggregates, not by eliminating them completely, but by “folding” them back.

“Just like when we are stressed by a heavy workload, cells can also be ‘stressed’ if they are asked to produce a large amount of protein,” said Dr. Edward Avezov of the Research Institute. of Dementia of the United Kingdom. Cambridge University.

“There are many reasons why this could be, for example, when they produce antibodies in response to an infection. We focused on emphasizing a component of the cells known as the endoplasmic reticulum, which is responsible for producing the about a third of our protein, and we assumed that this stress could cause incorrect folding. ”

The endoplasmic reticulum (ER) is a membrane structure found in mammalian cells. It performs a number of important functions, such as the synthesis, folding, modification, and transport of necessary proteins to the surface or out of the cell.

Dr. Avezov and his colleagues hypothesized that increased ER could lead to poor protein folding 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 surprised to see that the stress of the cell actually removed the aggregates, not degrading or cleaning them, but de-energizing them, which could allow them to fold again properly,” said Dr. Avezov. .

“If we can find a way to wake up this mechanism without stressing the cells, which could do more harm than good, then we could find a way to treat some dementia.”

The endoplasmic reticulum (ER) is a membrane structure found in mammalian cells. It performs a number of important functions, such as the synthesis, folding, modification, and transport of necessary proteins to the surface or out of the cell. The image is in the public domain

The main component of this mechanism appears to be one of a class of proteins known as thermal 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 speculates that this could help explain one of the most unusual observations within the field of dementia research. “Some studies have recently been done of people in Scandinavian countries who use saunas regularly, suggesting that they may be at lower risk of developing dementia. One possible explanation for this is that this mild stress triggers increased HSP activity, helping to correct tangled proteins “.

One of the factors that has previously hindered this field of research has been the inability to visualize these processes in living cells. Working with teams at Pennsylvania State University and the University of the Algarve, the team has developed a technique that allows them to detect incorrect folding of proteins in living cells. It is based on measuring the light patterns of a bright chemical on a nanosecond scale, one billionth of a second.

“It’s fascinating how measuring the life of our probe’s fluorescence at the nanosecond scale under a laser microscope makes otherwise invisible aggregates inside the cell obvious,” said Professor Eduardo Melo. one of the leading authors, from the University of the Algarve, Portugal.

About this research news in neurology

Author: Press Office
Source: Cambridge University
Contact: Press Office – University of Cambridge
Image: The image is in the public domain

Original research: Open Access.
“BiP-catalyzed stress-induced protein breakdown in the endoplasmic reticulum” by Edward Avezov et al. Communications of nature


See also

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BiP-catalyzed stress-induced endoplasmic reticulum-induced protein breakdown

Protein synthesis is supported by cellular machinery that ensures that polypeptides fold into their native conformation, while eliminating poorly folded aggregation-prone species. Protein aggregation is the basis of pathologies that include neurodegeneration.

The formation of aggregates is antagonized by molecular chaperones, with the cytoplasmic machinery resolving aggregates of insoluble proteins. However, it is unknown whether there is an endoplasmic reticulum (ER) -aggregating system in which ~ 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 protein aggregation probe system developed specifically with sub-organar resolution, we observed a steady-state accumulation of aggregates in the ER. Pharmacological induction of ER stress does not increase aggregates, but rather stimulates their elimination in hours.

We show that this disaggregation activity is catalyzed by the stress-sensitive ER molecular chaperone – BiP. This work reveals a non-redundant and hitherto unknown chain of the proteostasis-restoring ER stress response.

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