MSGID: 1:317/3 6275f602   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    '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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