The discovery may open up a potential new area for therapeutics.
It was believed that amyloid fibrils – rope-like structures made up of proteins sometimes known as fibres – are inert, but that there may be toxic phases during their formation which can damage cells and cause disease.
But in a paper published today [04 December 2009] in the Journal of Biological Chemistry, scientists at the University of Leeds have shown that amyloid fibres are in fact toxic – and that the shorter the fibre, the more toxic it becomes.
“This is a major step forward in our understanding of amyloid fibrils which play a role in such a large number of diseases,” said Professor Sheena Radford of the Astbury Centre for Structural Molecular Biology and the Faculty of Biological Sciences.
“We’ve revisited an old suspect with very surprising results. Whilst we’ve only looked in detail at three of the 30 or so proteins that form amyloid in human disease, our results show that the fibres they produce are indeed toxic to cells especially when they are fragmented into shorter fibres.”
Amyloid deposits can accumulate at many different sites in the body or can remain localised to one particular organ or tissue, causing a range of different diseases. Amyloid deposits can be seen in the brain, in diseases such as Parkinson’s and Alzheimer’s, whereas in other amyloid diseases deposits can be found elsewhere in the body, in the joints, liver and many other organs. Amyloid deposits are also closely linked to the development of Type II diabetes.
Professor Radford said: “Problems in the self-assembly process that results in the formation of amyloid are a natural consequence of longer life. In fact 85 per cent of all cases of disease caused by amyloid deposits are seen in those over the age of sixty or so.”
The study was funded by the Wellcome Trust and the Biotechnology and Biological Sciences Research Council (BBSRC), supporting a team that included both cell biologists and biophysicists.
The next stage of this work is to look at a greater number of proteins that form amyloid fibres in order to consolidate these findings, says co-author and cell biologist Dr Eric Hewitt. “What we’ve discovered is fundamental and offers a whole new area for those working on therapeutics in this area. We anticipate that when we look at amyloid fibres formed from other proteins, they may well follow the same rules.”
The team also hopes to discover why the shorter amyloid fibres are more toxic than their longer counterparts.
“It may be that because they’re smaller it’s easier for them to infiltrate cells,” says Dr Hewitt. “We’ve observed them killing cells, but we’re not sure yet exactly how they do it. Nor do we know whether these short fibres form naturally when amyloid fibres assemble or whether some molecular process makes them disassemble or fragment into shorter fibres.These are our next big challenges.”
Professor Radford and Dr Hewitt are available for interview.
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Notes for editors
1. These findings are published in a paper entitled Fibril Fragmentation Enhances Amyloid Toxicity in the Journal of Biological Chemistry a journal of the American Society for Biochemistry and Molecular Biology Journal. A copy of the paper is available on request.
2. The Astbury Centre for Structural Molecular Biology is an interdisciplinary research centre of the University of Leeds . It was founded to carry out international quality research in all aspects of structural molecular biology. The Centre brings together over fifty academic staff from various faculties of the University of Leeds who share common interests. It is named after W T Astbury, a biophysicist who laid many of the foundations of the field during a long research career at the University of Leeds (1928-1961) and who is widely credited with the definition of the field of molecular biology. www.astbury.leeds.ac.uk
3. The Faculty of Biological Sciences at the University of Leeds is one of the largest in the UK, with over 150 academic staff and over 400 postdoctoral fellows and postgraduate students. The Faculty is ranked 4th in the UK (Nature Journal, 457 (2009) doi :10.1038/457013a) based on results of the 2008 Research Assessment Exercise (RAE). The RAE feedback noted that “virtually all outputs were assessed as being recognized internationally, with many (60%) being internationally excellent or world-leading” in quality. The Faculty’s research grant portfolio totals some £60M and funders include charities, research councils, the European Union and industry. www.fbs.leeds.ac.uk
4. The 2008 Research Assessment Exercise showed the University of Leeds to be the UK ‘s eighth biggest research powerhouse. The University is one of the largest higher education institutions in the UK and a member of the Russell Group of research-intensive universities. The University’s vision is to secure a place among the world’s top 50 by 2015. ./
5. The Wellcome Trust is the largest charity in the UK . It funds innovative biomedical research, in the UK and internationally, spending around £600 million each year to support the brightest scientists with the best ideas. The Wellcome Trust supports public debate about biomedical research and its impact on health and wellbeing. www.wellcome.ac.uk
6. The Biotechnology and Biological Sciences Research Council (BBSRC) is the UK funding agency for research in the life sciences. Sponsored by Government, BBSRC annually invests around £450M in a wide range of research that makes a significant contribution to the quality of life for UK citizens and supports a number of important industrial stakeholders including the agriculture, food, chemical, healthcare and pharmaceutical sectors. BBSRC carries out its mission by funding internationally competitive research, providing training in the biosciences, fostering opportunities for knowledge transfer and innovation and promoting interaction with the public and other stakeholders on issues of scientific interest in universities, centres and institutes.
7. The Babraham Institute, Institute for Animal Health, Institute of Food Research, John Innes Centre and Rothamsted Research are Institutes of BBSRC. The Institutes conduct long-term, mission-oriented research using specialist facilities. They have strong interactions with industry, Government departments and other end-users of their research. www.bbsrc.ac.uk