Devastating brain diseases such as Creutzfeldt-Jakob disease (CJD) are caused by infectious protein particles called prions. Prions are proteins that have folded incorrectly, and they play a role in several brain diseases. Prions are capable of binding to normal proteins which causes tiny holes to form in the brain, giving brain tissue a sponge-like appearance. These holes result in progressive deterioration of brain function, dementia, and ultimately death.
While prions are known to cause the CJD, relatively little is known about how prions function in the brain, why prions are formed and how the misfolding occurs. Studies have been conducted in mouse and hamster models using non-human prions, which have aided understanding of prion-triggered disease, but the structure of nonhuman prions differs from their human counterparts, as does their mechanism of replication.
While therapeutic trials have been conducted, they have produced disappointing results. While there could be many possible reasons why that is the case, the lack of understanding of human prions is part of the problem. That problem may have now been solved. Researchers at Case Western Reserve University School of Medicine (CWRU) have successfully created artificial human prions in the lab.
“We report the synthesis of new human prion from the recombinant human prion protein expressed in bacteria in reaction seeded with sCJD MM1 prions and cofactor, ganglioside GM1,” wrote the authors.
The artificial human prions were infectious to humanized mice and caused brain disfunction after 459 and 224 days in the first and second passage respectively. The researchers appear to have created a particularly neurotoxic artificial human prion strain.
“Distinct biological and structural characteristics of our synthetic human prions suggest that subtle changes in the structural organization of critical domains, some linked to posttranslational modifications of the pathogenic prion protein (PrPSc), play a crucial role as a determinant of human prion infectivity, host range, and targeting of specific brain structures in mice models,” wrote the authors.
These artificial human prions could prove invaluable to researchers studying CJD and other prion-triggered diseases and could also be of great value to researchers studying Alzheimer’s and Parkinson’s diseases, which progress in a similar way to CJD.
“Our findings explain at 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 professor of pathology and neurology at CWRU School of Medicine, and senior study investigator, Jiri Safar, M.D.,
The paper – Artificial Creation of Human Prions in Vitro – has recently been published in the journal Nature Communications.