Scientists Have Synthesized the First Artificial Human Prion

The new findings offers treatment hope for brain-wasting diseases. (Credit: Case Western Reserve University)

Researchers at Case Western Reserve University School of Medicine have synthesized the first artificial human prion, a dramatic development in efforts to combat a devastating form of brain disease that has so far eluded treatment and cure. 

Prions are proteins that have folded incorrectly. They can bind to neighbouring normal proteins in the brain, triggering a domino effect that causes microscopic holes — turning brains into a sponge, which results in progressive deterioration, dementia, and certain death. There are numerous types of prion diseases in humans, the most common being Creutzfeldt-Jakob disease (CJD). 

Why, and how human prions misfolding occurs has been a mystery that the research team now may have solved with its new findings. 

“Until now, our understanding of prions in the brain has been limited,” said lead author, Jiri G. Safar, Professor of Pathology and Neurology at Case Western. “Being able to generate synthetic human prions in a test tube as we have done will enable us to achieve a much richer understanding of prion structure and replication.”


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Researchers already know how to make some forms of laboratory-rodents prions, but until now, none of these was infectious to humans as judged in experiments with humanised mice models. 

In their new paper, published in Nature Communications, the researchers describe their success in synthesising a new, highly destructive human prion protein expressed in E.coli bacteria. 

They also discovered an essential cofactor known as Ganglioside GM1 — a cell molecule which modulates cell-to-cell signalling — in triggering infectious replication and transmission of prion-based disease. This finding raises the hope for new therapeutic strategies using analogue medications with inhibitory or blocking effect on human prion replication. 

The researchers also demonstrated that the replication rate, infectivity, and targeting of specific brain structures by synthetic and naturally occurring prions is determined not by the presence of misfolded prions per se, but by particular variations and modifications in the molecule’s structure — specifically in an area known as the C terminal domain — which control the growth rate of infectious prions. 


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“Our findings explain the structural level the emergence of new human prions and provide a basis for understanding how seemingly subtle differences in misfolded protein structure and modifications affect their transmissibility, cellular targeting, and thus manifestation in humans”, said Safar. 

Currently, there is no treatment or cure for CJD. Symptoms are similar to those of Alzheimer’s disease, sometimes leading to misdiagnosis. These include dementia, memory loss, trouble walking, and impaired vision.

The occurrence of human prion diseases peaks at ages 60-65, accounting for approximately 1 in 10,000 deaths worldwide. Despite their relative rarity, human prion diseases have gained considerable notoriety and relevance because they display characteristics of neurodegenerative diseases but are infectious. Furthermore, they can spread not only between humans but also from animals to humans by an infectious agent that is highly resistant to inactivation.

Previous prion studies were carried out with laboratory nonhuman prions on mouse and hamster models. While this approach was useful for a general understanding of prion-triggered disease, human prions are different from these strains in both structure and mechanism of replication.

Several recent therapeutic trials of human prion diseases have failed. Although these disappointing results may have occurred for multiple reasons, they demonstrate that the results from animal or cellular prion models do not automatically apply to human prions. Creating artificial human prions will allow researchers to engage in an apples-to-apples study process, opening the door to more complete insights into how prions unleash their destructive force, potentially resulting in medications that can stop the disease in its tracks. And since Parkinson’s and Alzheimer’s diseases spread through the brain in similar fashion as CJD, new inroads against these conditions are possible as well.

This current paper is a continuation of Dr. Safar’s research from 1998, where he published a paper on a “prion shape detector” published in Nature Medicine, which received global coverage.