Summary: Instead of destroying protein aggregates, the study reveals a new mechanism that reverses and reverses their accumulation.
A source: University of Cambridge
It is often said that a little stress will be good for you. Scientists have now discovered a new mechanism that can help prevent the accumulation of protein shells commonly found in dementia, and show that the same can happen to cells.
A feature of diseases such as Alzheimer’s and Parkinson’s, which are common neurodegenerative diseases, is the accumulation of incorrectly folded proteins. In Alzheimer’s disease, these proteins, such as amyloid and mountains, 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 people, cells perform a form of quality control to ensure that proteins are folded properly and that incorrectly folded proteins are destroyed. However, in neurodegenerative diseases, this system can be disrupted and lead to consequences.
As the world’s population ages, the number of people with dementia is increasing, which exacerbates the search for effective drugs. However, progress is slow, and there are no drugs to prevent or eliminate the accumulation of aggregates.
In a study published today Nature CommunicationsA team led by researchers at the University of Cambridge’s Institute for the Study of Dementia in the UK has identified a new mechanism to reverse the accumulation of aggregates, rather than completely destroying them.
“Just as we are stressed by a heavy load, cells can be” stressed “if they are called upon to produce large amounts of protein,” he explained. Edward Avezov is from the Institute of Dementia at Cambridge University.
“There are many reasons for this, such as when they produce antibodies in response to an infection. We highlighted a part of the cells called the endoplasmic reticulum, which is responsible for producing one-third of the proteins, and thought that this stress could lead to improper folding.
The endoplasmic reticulum (ER) is a membrane structure found in mammalian cells. It performs a number of important functions, such as synthesizing, folding, modifying and transporting the necessary proteins on or off the surface of the cell.
Dr. Avezov and colleagues suggest that focusing on ER may lead to improper folding and aggregation of the protein, reducing its ability to function properly and leading to increased aggregation.
They were astonished to see the opposite.
“We were amazed that the pressure on the cell allowed the units to fold properly, not by degrading or cleaning them, but by opening the units,” he said. Avezov.
“If we can find a way to awaken this mechanism, without focusing on the cells, it can do more harm than good – then we can find a way to treat some dementia.”
A key component of this mechanism appears to be a class of proteins called thermal shock proteins (HSPs), many of which are formed when cells are exposed to temperatures above normal growth temperatures and in response to stress.
Dr. Avezov believes that this will help explain one of the most unusual observations in the field of dementia. “A recent study of regular sauna users in the Scandinavian countries suggests that they are less likely to develop dementia. One possible explanation for this is that mild stress increases the activity of HSPs and helps to repair entangled proteins.
So far, one of the obstacles to this research has been the inability to imagine these processes in living cells. Working with teams from the University of Pennsylvania and the University of Algarve, the team developed a method that allowed them to detect protein folding in living cells. It relies on nanoseconds to measure light samples of a bright chemical in a billionth of a second.
Eduardo Melo, a professor at the University of Algarve (Portugal), one of the leading authors, says:
News about neuroscience research
Author: Press service
A source: University of Cambridge
The connection: Press Service – University of Cambridge
Photo: Image in public domain
Original study: Open access.
Edward Avezov Nature Communications
Stress-induced protein disaggregation in the endoplasmic reticulum catalyzed by BiP
Protein synthesis is supported by cellular devices that allow polypeptides to bend to their original conformation, while eliminating improperly folded, aggregated species. Protein aggregation is the basis of pathologies, including neurodegeneration.
The formation of aggregates is antagonized by molecular chaperones, the cytoplasmic mechanism dissolves insoluble protein aggregates. However, it is unknown whether ~ 30% of the proteome has an analogous disaggregation system in the synthesized endoplasmic reticulum (ER).
Here we show that different types of mammalian cell types, including neurons, are equipped with the ability to resolve ER, protein aggregates under stress.
Using a specially designed protein aggregation research system with sub-organelle resolution, we observe the accumulation of a stable aggregate in the ER. The pharmacological induction of ER stress does not increase the aggregates, but rather stimulates their clearance within a few hours.
We assume that this disaggregation activity is catalyzed by stress-responsive ER molecular chaperone – BiP. This activity reveals a previously unknown, non-excessive band of proteostasis-restoring ER stress response.