A team of scientists at Case Western Reserve University School of Medicine has created the first artificial human prion.

Human prions — proteins that have folded incorrectly — cause invariably fatal, rapidly progressive neurodegenerative diseases; the most common being Creutzfeldt-Jakob disease.

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.

“Until now our understanding of prions in the brain has been limited,” said senior author Professor Jiri G. Safar, from Case Western Reserve School of Medicine.

“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 lab-rodent prions, but until now, none of these was infectious to humans as judged in experiments with humanized mice models.

In their new study, Professor Safar and colleagues synthesized a new, highly destructive human prion from a genetically engineered human prion protein expressed in E. coli bacteria.

The researchers 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 team 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.

“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,” Professor Safar said.

The study was published in the journal Nature Communications.

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Chae Kim et al. 2018. Artificial strain of human prions created in vitro. Nature Communications 9, article number: 2166; doi: 10.1038/s41467-018-04584-z