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Ten-foot tall microscopes helping combat world’s worst diseases

 October 31, 2018 | Simon Jenkins

The century-long mission to understand how the proteins which underpin amyloid-based diseases like Alzheimer’s, Huntington’s and Parkinson’s has taken major steps forward in the last 12 months.

High-powered microscopes using electrons instead of light to ‘see’ the actual shape of samples put under them, at near atomic-levels of detail, have only recently become available to UK scientists. The UK has invested heavily in the ‘game-changing’ cryo-electron microscopes, but there are still fewer than 25 of the multi-million pound instruments in UK universities and research institutes.

The two at the University of Leeds, funded by the University itself and Wellcome, are the only ones of their kind in the north of England.They have already proved their worth as a key tool for scientists who have used them in a number of research projects, but have just delivered their biggest success yet: to reveal the structure of amyloid – a build-up of abnormal proteins in the body that causes disease.

There are less than ten good quality images and structures of these kinds of proteins available to study in the world. This means the Leeds research makes a significant contribution to scientists’ understanding of how the proteins’ form aggregates and how they might contribute to amyloid disease.The Leeds study was the first to provide a high quality image of the ß2microglobulin protein using cryo-electron microscopy.

The images and 3D structures of the protein aggregates – which the Leeds scientists showed formed long, twisted fibres – has been published in the journal Nature Communications.The protein is normally involved in a healthy immune system, but can assemble into the pain-causing amyloid fibres in people who undergo long term dialysis for kidney failure. When they lodge in people’s joints they can cause osteoarthritis.

The publication of the new amyloid structure represents a major contribution to the field of protein science, showing two very different forms of the same protein in healthy and disease form. It is anticipated the findings will be used by drug manufacturers and research groups internationally who strive to fund cures for amyloid diseases of all types.

Professor Sheena Radford FMedSci, FRS and Professor Neil Ranson from the University’s Astbury Centre for Structural Molecular Biology, led the five year programme to image the protein fibres and show their 3D structure. Their findings showed that protein fibres with different forms can be assembled by different packing of a common structural building block. This explains one of the major conundrums in amyloid research which is how so many different forms of fibre can come from the same protein sample.

Professor Radford said: “Over the past six decades since the first electron microscopy pictures of amyloid were created, scientists have progressed from working with blurred low-resolution images to our razor sharp 3D images and structures, thanks to modern advances in cryo-electron microscopy.

“Now we know exactly where each kink and point is on the protein, we may be able to develop compounds which lock tightly to it, or disrupt it, and find out how the fibres contribute to disease. It’s the equivalent of going from trying to make two balloons stick together to having two cogs rotating perfectly with each other.”

She added: “We’ve used cryo-electron microscopy not only to uncover the shape and structure of amyloid proteins, but also how they grow and intertwine with each other like the strands in a rope to form larger assemblies. This knowledge is going to be crucial for knowing how to deal with them.”

Ten-foot tall microscopes helping combat world’s worst diseases