'Stressed' cells offer clues to eliminating build-up of toxic proteins
in dementia
Date:
May 6, 2022
Source:
University of Cambridge
Summary:
It's often said that a little stress can be good for you. Now
scientists have shown that the same may be true for cells,
uncovering a newly- discovered mechanism that might help
prevent the build-up of tangles of proteins commonly seen in
dementia. Scientists have identified a new mechanism that appears
to reverse the build-up of aggregates, not by eliminating them
completely, but rather by 'refolding' them.
FULL STORY ==========================================================================
It's often said that a little stress can be good for you. Now
scientists have shown that the same may be true for cells, uncovering
a newly-discovered mechanism that might help prevent the build-up of
tangles of proteins commonly seen in dementia.
==========================================================================
A characteristic of diseases such as Alzheimer's and Parkinson's - - collectively known as neurodegenerative diseases -- is the build-up 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 carry out a form of quality control to ensure
that proteins are correctly folded and that misfolded proteins are
destroyed. But in neurodegenerative diseases, this system becomes
impaired, with potentially devastating consequences.
As the global population ages, an increasing number of people are being diagnosed with dementia, making the search for effective drugs ever more urgent. However, progress has been slow, with no medicines yet available
that can prevent or remove the build-up of aggregates.
In a study published today in Nature Communications, a team led
by scientists at the UK Dementia Research Institute, University of
Cambridge, has identified a new mechanism that appears to reverse the
build-up of aggregates, not by eliminating them completely, but rather by 'refolding' them.
"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," explained Dr Edward Avezov from the UK Dementia Research Institute at the University of Cambridge.
========================================================================== "There are many reasons why this might be, for example when they
are producing antibodies in response to an infection. We focused on
stressing a component of cells known as the endoplasmic reticulum,
which is responsible for producing around a third of our proteins --
and assumed that this stress might cause misfolding." The endoplasmic reticulum (ER) is a membrane structure found in mammalian cells. It
carries out a number of important functions, including the synthesis,
folding, modification and transport of proteins needed on the surface or outside the cell. Dr Avezov and colleagues hypothesised that stressing
the ER might lead to protein misfolding and aggregation by diminishing
its ability to function correctly, leading to increased aggregation.
They were surprised to discover the opposite was true.
"We were astonished to find that stressing the cell actually eliminated
the aggregates -- not by degrading them or clearing them out, but
by unravelling the aggregates, potentially allowing them to refold
correctly," said Dr Avezov.
"If we can find a way of awakening this mechanism without stressing the
cells - - which could cause more damage than good -- then we might be
able to find a way of treating some dementias." The main component of
this mechanism appears to be one of a class of proteins known as heat
shock proteins (HSPs), more 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 might help explain one of the more unusual observations within the field of dementia research. "There have been
some studies recently 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 a higher activity of HSPs, helping correct tangled proteins."
One of the factors that has previous hindered this field of research has
been the inability to visualise these processes in live 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 live cells. It relies on measuring light patterns
of a glowing chemical over a scale of nanoseconds -- one billionth of
a second.
"It's fascinating how measuring our probe's fluorescence lifetime on the nanoseconds scale under a laser-powered microscope makes the otherwise invisible aggregates inside the cell obvious," said Professor Eduardo
Melo, one of the leading authors, from the University of Algarve,
Portugal.
The research was supported by the UK Dementia Research Institute, which receives its funding from the Medical Research Council, Alzheimer's
Society and Alzheimer's Research UK, as well as the Portuguese Foundation
for Science and Technology.
========================================================================== Story Source: Materials provided by University_of_Cambridge. The original
text of this story is licensed under a Creative_Commons_License. Note:
Content may be edited for style and length.
========================================================================== Journal Reference:
1. Eduardo Pinho Melo, Tasuku Konno, Ilaria Farace, Mosab Ali
Awadelkareem,
Lise R. Skov, Fernando Teodoro, Teresa P. Sancho, Adrienne W. Paton,
James C. Paton, Matthew Fares, Pedro M. R. Paulo, Xin Zhang, Edward
Avezov. Stress-induced protein disaggregation in the endoplasmic
reticulum catalysed by BiP. Nature Communications, 2022; 13 (1)
DOI: 10.1038/s41467-022-30238-2 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/05/220506102618.htm
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