C. elegans model system accelerates discovery of amyloid inhibitors

An international team led by researchers at the University of Toronto has developed an efficient and robust system, using the C. elegans nematode, to screen for compounds that can stop the growth of amyloid proteins. Through their own screen of over 2,500 compounds, the team found 40 that demonstrate the ability to inhibit amyloid formation.

Amyloid proteins and peptides are associated with more than 50 human diseases, including common neurodegenerative diseases like Parkinson's and Alzheimer's, and more rare ones like Huntington's.

Environmental factors, genetic mutations and other unknown factors can cause amyloid proteins or peptides to clump inside or outside the cell, forming structures that incrementally increase in complexity. These structures result in highly damaging protein aggregations, such as the Lewy bodies of Parkinson's or the beta-amyloid plaques found in Alzheimer's patients. Currently, there is no cure for diseases caused by amyloids, with existing therapies focused on symptom alleviation instead of prevention."

Muntasir Kamal, co-first author on the study and PhD graduate of U of T's Donnelly Centre for Cellular and Biomolecular Research

The study was published recently in the journal Nature Communications.

In an effort to treat amyloid-associated diseases, the research team worked towards finding small molecules that bind to amyloids -; and thereby prevent them from binding to other molecules that can help them aggregate. An example of a compound that can do this is the Congo red dye used to stain amyloids that form in nematodes used for research.

The team searched for additional compounds that outcompete aggregate-forming molecules in nematodes when it comes to binding to amyloids. The crucial difference between compounds that prevent amyloids from aggregating and those that help them do this is that the former are not able to grow into more complex structures. Instead, they function like a harmless placeholder in the space where the aggregate-forming molecules would attach.

Showing that the popular model system C. elegans could be used to screen small molecules for amyloid binders is an exciting breakthrough in the pursuit of treatments for diseases linked to amyloids. The reliability of the nematode screening system was confirmed for many of the newly discovered amyloid binders through in vitro experiments, indicating that the results of study could potentially be applied to humans.

"Most primary screens for amyloid binders have been conducted in cell-based or cell-free in vitro assays," said Kamal. "When it comes to animal models, mice and rats are most commonly used to test experimental amyloid inhibitors. They both have their advantages, but neither compares to the free-living nematode C. elegans in terms of how quickly compounds can be screened with the worm model. It only takes one week to conduct an amyloid inhibitor screen with nematodes, which offer a more accurate representation of disease states than a petri dish."

"We've developed a platform to rapidly screen compounds for amyloid growth suppressors," said Peter Roy, principal investigator on the study and professor of molecular genetics at the Donnelly Centre and U of T's Temerty Faculty of Medicine. "This platform can be used in preclinical studies to inform drug therapies. Ultimately, we hope to see results from testing amyloid binders in nematodes translate to treating neurodegenerative diseases in humans."

This research was supported by the Canada Research Chairs Program, the Canadian Institutes of Health Research, the John Templeton Foundation and UK Research and Innovation.