2020 Research Grants – Blog Series – Part 1
Launching our new series of blogs about our latest research round – John Telford, lay advisor on our Scientific Advisory Panel, writes about the first award :
Don’t ‘Diss’ the Dustman …
This theme keeps recurring: the key to MSA could be incompetent rubbish collection. Getting to the bottom of this at the cellular level is what this project is all about.
Dr Maria Xilouri from the Biomedical Research Foundation, Academy of Athens is the lead researcher for this project.
Background to the research – taking out the rubbish
‘Bad’ forms of alpha-synuclein are part of the ‘rubbish’ we are talking about. The functions of proteins, which are long molecules made up of amino acids, depend on how they are folded. Sometimes they become misfolded and in this state can be toxic. Clearly this toxic rubbish needs to be removed.
MSA results from certain cells in the brain dying off, the cells that are affected are those cells – called glial cells – which nourish and physically support the nerve cells. And it is alpha-synuclein, misfolded in different ways, which apparently is the culprit. Deposits of molecules of alpha synuclein in aggregated form are found in brain cells and it is thought that these are the result of the cells trying but failing to clear up and dispose of these misfolded proteins. It is like putting your rubbish into black bags but not having the dustman come round to collect them.
One of the main rubbish disposal systems in the cells of our body is known as the Autophagy-lysosome pathway (ALP for short). For some reason we put the accent on the ‘o’ in the first word and the ‘y’ in the second: AutOphagy, LYsosome. When the system is behaving normally, any bits of rubbish in a cell, such as old proteins that have served their purpose or fragments of other material that are the result of cellular processes, are packaged into microscopic containers called lysosomes. This rubbish is then worked on by enzymes inside the lysosomes to break them down into smaller molecules that can be more easily and safely recycled.
Two broad aims
The first broad aim of this project is to understand better the details of what is going on in the case of MSA. It appears that the ALP is not working properly. But why not? Early results suggest that misfolded alpha-synuclein (along with another rogue protein named p25alpha) interferes with autophagy if it can get a toe-hold. So it looks like there is a vicious circle operating: The ALP is meant to clear away these rogue proteins. But, once these proteins are present, they can compromise an ALP that is already functioning below par. But is it a pre-existing vulnerability of the ALP or the ingress of a particular strain of misfolded protein that kicks it all off? Or does it need both?
The second broad aim is to see whether the ALP can be given a helping hand to restore the rubbish-collection function to such an extent that the alphasynuclein and p25alpha are effectively removed and the glial cells remain healthy and can continue to play their vital role.
This blog is reproduced in full on our website HERE.
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