There are currently no effective treatments for prion diseases, a family of fatal neurodegenerative conditions caused by accumulations of misfolded copies of a naturally occurring protein. But now, there is finally an effective way to test for them.
As reported in the journal PLOS ONE, a team of scientists who have been working on prion detection for nearly 20 years have demonstrated that their unique, synthetic-molecule-based approach can isolate prion proteins in body fluids sampled from infected animals. This finding – which confirms that their test is the only published testing method capable of quick, noninvasive prion detection in living subjects – is a momentous milestone in the evolution of a biomedical technology with far-ranging applications.
“Our peptoid beads have the ability to detect the misfolded proteins that act as infectious agents, so it could have a significant impact in the realm of prion diseases, but we have also shown that it can seek out the large aggregated proteins that are the disease agents in Alzheimer’s and Parkinson’s diseases, among others” said Ronald Zuckermann, an early pioneer of peptoids and one of the research team’s founding members. Zuckermann is now a senior scientist at Lawrence Berkeley National Laboratory (Berkeley Lab)’s Molecular Foundry. “Prion diseases are rare, but there are many misfolded protein-based diseases, which affect millions of people, that are also very poorly understood. And like prion diseases, we need a way to diagnose these slow-onset conditions in the years before symptoms arise.”
Peptoids are artificial compounds made to mimic peptides, the short chains of amino acids that serve as protein building blocks. The team’s beads are tiny magnets covered in peptoids that mimic part of the prion protein. When added to a liquid sample, the peptoid-bead units latch onto misfolded prion protein aggregates but leave normal proteins alone.“It’s like Velcro,” said co-author Michael Connolly, senior scientific engineer of the Molecular Foundry’s biological nanostructures group. “The aggregated misfolded protein has multiple hooks – multiple binding sites – that will attach to the bead, which is like the complementing sheet. But the natural, correctly folded protein only has a single hook, so its binding affinity is much less.”
Once bound, the misfolded proteins are pulled out of the liquid magnetically, and then run through a test called the misfolded protein assay (MPA), which was developed by scientists at Novartis and senior author Adriano Aguzzi, a neuropathologist and renowned expert in prion diseases.
“On top of potentially detecting asymptomatic disease carriers, the peptoid-bead MPA could be optimized to screen blood and blood products in a cheap and fast manner, a capability that will be very important for avoiding accidental transmission in case of a new prion disease outbreak,” said first author Simone Hornemann, a senior researcher in Aguzzi’s group at the University Hospital Zurich’s Institute of Neuropathology. “This assay could also be modified to test deer and elk for chronic wasting disease (CWD), a prion disease that is considered as a global epidemic in these animals.”
