• 'Stressed' cells offer clues to eliminat

    From ScienceDaily@1:317/3 to All on Fri May 6 22:30:40 2022
    '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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