Finding May Shed Added Light On, Offer Treatment Hope for Brain-Wasting Diseases
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 CWRU 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 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.
Safar was lead author of a pioneering paper on a “prion 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.
The Latest on: Artificial human prion
via Google News
The Latest on: Artificial human prion
- ‘Mini’ U6 Pol III promoter exhibits nucleosome redundancy and supports multiplexed coupling of CRISPR/Cas9 effectson March 20, 2020 at 8:19 am
RNA polymerase III (Pol III) promoters express short non-coding RNAs and have been adopted for expression of microRNA, interference RNA, and CRISPR single guide RNA (sgRNA). Vectors incorporating H1 ...
- Fascinating Facts You Never Knew About The Human Brainon March 19, 2020 at 6:07 am
A study of one million students in New York showed that students who ate lunches that did not include artificial ... shows that humans carry genes that help protect the brain from prion diseases ...
- Could disease pathogens be the dark matter behind Alzheimer's disease?on March 17, 2020 at 5:00 pm
Researchers discuss the idea that bacteria, viruses or other infectious pathogens may play a role in Alzheimer's disease. For researchers investigating Alzheimer's Disease (AD), a devastating ...
- Brain-doping produced by your own bodyon March 16, 2020 at 1:12 pm
leading to a measurable improvement in cognitive performance in humans and mice," explained Ehrenreich. The self-reinforcing cycle of mental and cognitive challenge, activity-induced hypoxia and ...
- New diagnostic tech uses AI to screen blood for over 1400 pathogenson March 15, 2020 at 11:45 pm
Karius has developed a proprietary method for efficiently extracting the mcfDNA from blood samples and masking the signal from human DNA and any environmental ... genomic data points generated. With ...
- Researchers forge a new weapon to fight parasites and other infectionson March 12, 2020 at 7:05 am
But because parasites are more closely related to humans than other pathogens ... viral, fungal and prion—that cause all kinds of illnesses, from common colds and flus to such potentially ...
- Layered liquids: Reaction chambers for gene regulationon March 12, 2020 at 5:06 am
"And we also realized a potential link to human disease." Lge1 has a functional counter-part in humans, called WAC. This protein also behaves like a liquid and when mutated causes DeSanto ...
- Readers respond to Notre Dame’s uncertain futureon February 29, 2020 at 10:27 am
Reader Brian Mahood was surprised to learn that prions could diminish or block communication between brain cells. “This might be an irreversible event and thus leave one with ‘holes’ in one ...
- Staining, straining and restraining prionson April 26, 2019 at 5:37 pm
Beyond all academic curiosity, such an understanding would be instrumental for assessing the risk to humans of prion diseases spreading among animals. An important defining trait of strains is ...
via Bing News