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This century-old mission aimed at understanding how the proteins responsible for amyloid-based diseases such as Alzheimer's, Huntingdon's and Parkinson's diseases has progressed significantly over the last 12 months, thanks to a revolution in a powerful microscopy technique used by scientists.
The very powerful microscopes using electrons instead of light to "see" the actual shape of the samples placed beneath them, at a level of detail close to the atom, are only recently available for British scientists.
The United Kingdom has invested heavily in revolutionary cryo-electron microscopes, but there are still less than 25 multi-million pound instruments in British universities and research institutes.
The two instruments of the University of Leeds are the only ones of its kind in the north of England.
They have already proven themselves as an essential tool for scientists who have used them in a number of research projects, but have just achieved their greatest success: revealing the structure of amyloid, an accumulation of abnormal proteins in the body that causes the disease.
There are fewer than 10 good quality images and structures of this type of protein in the world. Leeds research has thus made a significant contribution to scientists' understanding of how proteins form aggregates and could contribute to amyloid disease.
The images and three-dimensional structures of the protein aggregates, which, according to Leeds scientists, formed long, twisted fibers, were published in the journal Nature Communications.
The implicated protein, β2-microglobulin, is normally involved in a healthy immune system, but can assemble into amyloid fibers causing pain in long-term dialysis patients for renal failure. When they lodge in the joints, they can cause osteoarthritis.
The results are expected to be used by drug manufacturers and international research groups seeking to fund treatments for amyloid diseases of all types.
Sheena Radford and Neil Ranson, of the Astbury Center for Structural Molecular Biology of the University, led the five-year program to image protein fibers and show their 3D structure.
The couple was supported by colleagues from Leeds, Josh Boardman, who was an undergraduate student in biochemistry at the time.
The study also involved a long-standing collaboration with Bob Griffin, a professor at the Massachusetts Institute for Technology, specializing in another method of advanced biological analysis of biological material: nuclear magnetic resonance in the state solid.
"Over the past six decades, since the creation of the first electron microscopic images of amyloid, scientists have moved from working with low-resolution blurred images to our razor-sharp three-dimensional images and structures, thanks to modern advances in cryo-electronic microscopy. " said Radford. "Now that we know exactly where the protein's landmarks are, we may be able to develop compounds that close it tightly or disrupt it, and discover how fiber contributes to the disease. 39 equivalent of trying to We used cryo-electron microscopy to discover the shape and structure of amyloid proteins, but also to determine how they develop and intertwine as stands in a rope to form more This knowledge will be crucial to know how to treat them. "
"Until about a year ago, scientists knew that the structure looked more or less like a scale, but we've now shown that it's a lot more complex than that." We're now starting to see how different proteins fold into different forms and how these vary with each disease they cause, "said Ranson. "The additional details we have discovered allow us to begin to understand the capabilities of these proteins to cause disease.It is also known that amyloid fibers have the strength of steel, and we now understand its structure. Perhaps we could create new biomaterials inspired by their structure, which is an excellent example of where cryogenic microscopy can have additional benefits. "
Knowing the structure of the protein in the level of detail provided by Leeds researchers, and measuring these differences between different types of amyloid disease and different patients, could also allow doctors to determine who is most at risk, which means that Treatment can be targeted. those who need it most.
The next step for the scientific community is to start identifying and developing inhibitory compounds, which can control protein assembly in amyloid.
Further laboratory testing, clinical trials, regulatory approval and participation of a drug developer would still be needed before the drugs could be marketed, but significant advances in terms of image clarity and Understanding the amyloid folding structure represents a big step forward.
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