Researchers create first artificial human prion

June 5, 2018, Case Western Reserve University
Synthetic human prions accumulating in the brain of humanized transgenic mice. Credit: Case Western Reserve School of Medicine

Case Western Reserve University School of Medicine researchers 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 a cure. The new findings are published in Nature Communications.

Prions are proteins that have folded incorrectly. They can bind to neighboring normal proteins in the brain, triggering a domino effect that causes microscopic holes, turning brains into sponge, resulting 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 prion mis-folding occurs has been a mystery that the Case Western Reserve investigative team may have solved with its new findings.

"This accomplishment represents a watershed," said Jiri G. Safar, MD, professor of pathology and neurology at Case Western Reserve School of Medicine and the study's lead author. "Until now our understanding of prions in the brain has been limited. 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. This is crucial for developing inhibitors of their replication and propagation throughout the brain, which is essential for halting prion-based brain disease."

Researchers already know how to make some forms of laboratory-rodent prions, but until now, none of these was infectious to humans as judged in experiments with humanized mice models. In their new paper, the researchers describe their success in synthesizing a new, highly destructive human prion from a genetically engineered 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 signaling—in triggering infectious replication and transmission of prion-based disease. This finding raises the hope for new therapeutic strategies using analog 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 mis-folded 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. "Our findings explain at the structural level the emergence of new human prions and provide a basis for understanding how seemingly subtle differences in mis-folded 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 mis-diagnosis. 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 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 in its tracks. And since Parkinson's and Alzheimer's diseases spread through the in similar fashion as CJD, new inroads against these conditions are possible as well.

Safar was lead author of a pioneering paper on a " shape detector" published in Nature Medicine in 1998, which received extensive global coverage and has been highly quoted ever since. The current paper in Nature Communications is a continuation of this ground-breaking research.

Explore further: Microglia are key defenders against prion diseases

More information: Chae Kim et al, Artificial strain of human prions created in vitro, Nature Communications (2018). DOI: 10.1038/s41467-018-04584-z

Related Stories

Microglia are key defenders against prion diseases

May 17, 2018
Prion diseases are slow degenerative brain diseases that occur in people and various other mammals. No vaccines or treatments are available, and these diseases are almost always fatal. Scientists have found little evidence ...

Small loop in human prion protein prevents chronic wasting disease

February 23, 2015
Chronic wasting disease (CWD)—an infectious disease caused by prions—affects North American elk and deer, but has not been observed in humans. Using a mouse model that expresses an altered form of the normal human prion ...

Mutant prion protein could help reveal neurodegenerative disease mechanisms

November 23, 2016
For the first time, scientists have isolated a mutated prion protein that can multiply in the lab but not in living animals, according to a PLOS Pathogens study. The mutant prion provides new insights into the mechanisms ...

Researchers find infectious prions in Creutzfeldt-Jakob disease patient skin

November 22, 2017
Creutzfeldt-Jakob disease (CJD)—the human equivalent of mad cow disease—is caused by rogue, misfolded protein aggregates termed prions, which are infectious and cause fatal damages in the patient's brain. CJD patients ...

Recombinant human prion protein inhibits prion propagation

October 9, 2013
Case Western Reserve University researchers today published findings that point to a promising discovery for the treatment and prevention of prion diseases, rare neurodegenerative disorders that are always fatal. The researchers ...

Molecular link between Parkinson's disease and prion diseases

September 15, 2017
Parkinson's disease and prion diseases are very different as regards both origins and course. Nonetheless, a research group of SISSA, headed by Professor Giuseppe Legname, has discovered an unexpected and important link between ...

Recommended for you

New study finds 'timing cells' in the brain may underlie an animal's inner clock

October 23, 2018
Are you taking your time when feeding your pet? Fluffy and Fido are on to you—and they can tell when you are dawdling.

Neurons reliably respond to straight lines

October 23, 2018
Single neurons in the brain's primary visual cortex can reliably detect straight lines, even though the cellular makeup of the neurons is constantly changing, according to a new study by Carnegie Mellon University neuroscientists, ...

Scientists reveal new details of how a naturally occurring hormone can boost memory in aging mice

October 23, 2018
A Columbia study in mice has revealed new details of how a naturally occurring bone hormone reverses memory loss in the aging brain. These findings about the hormone, called osteocalcin, stand to spur further investigations ...

Mutation in common protein triggers tangles, chaos inside brain cells

October 23, 2018
A pioneer in the study of neural cells revealed today (Oct. 23, 2018) how a single mutation affecting the most common protein in a supporting brain cell produces devastating, fibrous globs. These, in turn, disturb the location ...

Nerve-on-a-chip platform makes neuroprosthetics more effective

October 23, 2018
EPFL scientists have developed a miniaturized electronic platform for the stimulation and recording of peripheral nerve fibers on a chip. By modulating and rapidly recording nerve activity with a high signal-to-noise ratio, ...

The smell of lavender is relaxing, science confirms

October 23, 2018
Lavender works its relaxing magic all around us: from garden borders to bath bombs to fabric softener. But why not in our hospitals and clinics? And what is the science behind the magic?

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

Anonym518498
5 / 5 (1) Jun 05, 2018
I hope this beast doesn't escape the lab

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.