Size matters: amyloid fibrils toxic to cells, especially as fragments, researchers find
4 December 2009
Scientists from the University of Leeds have shown that amyloid fibrils - fine fibres of protein implicated in a number of debilitating diseases - are not inert as previously thought, but may in fact be toxic to cells, especially when they are in small fragments.
This work could help researchers trying to prevent or treat diseases caused by the accumulation of amyloid deposits. While it's possible that stabilising the full-size fibril may help to prevent cell death, a new route to therapy may be preventing the fibrils from forming altogether or breaking once formed.
Amyloid fibrils are made up of any one of around 30 proteins or peptides. Yet despite the different building blocks, all such fibrils fold up in a similar way.
Dependent on the protein or peptide that assembles into fibrils, amyloid can accumulate at a number of different sites in the body and cause disease. Deposits in the brain are associated with Alzheimer's disease and Parkinson's disease, whereas those in the pancreas are closely linked to the development of type II diabetes.
Researchers had originally thought that intermediates in the process of making fibrils - rather than the fibrils themselves - caused the death of cells near to them. But the new findings suggest that the fibrils themselves can also be toxic, especially if they're broken down into small pieces.
"We've revisited an old suspect with very surprising results," says Professor Sheena Radford, who led the study.
"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."
In future work the researchers will investigate why the shorter fibrils are more toxic than the longer ones. "It may be that because they're smaller it's easier for them to infiltrate cells," says Dr Eric Hewitt, a co-author of the paper.
It's also unclear how the shorter amyloid fragments arise, so the researchers will explore whether these fragments form during assembly of the fibrils, or whether they are a result of larger fibrils being broken down.
This study was funded by the Wellcome Trust and the Biotechnology and Biological Sciences Research Council.
Image: Microscopic view of amyloid fibrils. These protein fibres are associated with a number of diseases in humans. Credit: Wei-Feng Xue, University of Leeds.
Reference
Xue, W-F et al. Fibril fragmentation enhances amyloid toxicity. J Biol Chem 2009;284(49):34272-82.