Researchers develop rapid screen for new molecules that suppress disease-causing amyloids

An international team led by researchers at the University of Toronto has developed a system to screen for compounds that can stop the growth of amyloid proteins, using the C. elegans nematode. 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,” said Muntasir Kamal, co-first author on the study and PhD graduate of U of T’s Donnelly Centre for Cellular and Biomolecular Research.

“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,” Kamal said.

The study was published in the journal Nature Communications.

The team looked for small molecules that could bind to amyloids, and in turn, prevent the amyloids from binding to other molecules that help them aggregate.

The researchers also sought compounds that could outcompete aggregate-forming molecules in the nematodes. Compared to compounds that support amyloid aggregation, compounds that prevent amyloid aggregation don’t grow into more complex structures. Instead, they function like a harmless placeholder where the aggregate-forming molecules would otherwise attach.

The nematode screening system’s reliability was confirmed for many of the newly discovered amyloid binders through in vitro experiments (done in the lab instead of in a living organism. This work suggests the study’s results could potentially be applied to humans.

“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,” said Kamal.

“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.