The length of amyloid fibrils found in diseases such as Alzheimer and Parkinson appears to play a role in the degree of their toxicity, according to researchers at the University of Leeds. Their findings are published in The Journal of Biological Chemistry in a paper titled “Fibril Fragmentation Enhances Amyloid Cytotoxicity.”
Sheena Radford, Ph.D., and colleagues systematically analyzed the effects of fragmentation on three of the 30 or so proteins that form amyloid in human diseases. Their results showed that in addition to the expected relationship between fragmentation and the ability to seed, the length of fibrils also correlated with their ability to disrupt membranes and reduce cell viability. This was evident even when there were no other changes in molecular architecture.
Co-author, Eric Hewitt, Ph.D., says that while the findings provide scientists with unexpected new insights for the development of therapeutics against amyloid deposit-related diseases, the next stage of research will involve looking at a greater numbers of the proteins that form amyloid fibrils. “We anticipate that when we look at amyloid fibers formed from other proteins, they may well follow the same rules.”
“It may be that because they’re smaller it’s easier for them to infiltrate cells,” Dr. Hewitt suggests. “We’ve observed them killing cells, but we’re not sure yet exactly how they do it. Nor do we know whether these short fibers form naturally when amyloid fibers assemble or whether some molecular process makes them disassemble or fragment into shorter fibers. These are our next big challenges.”