Hot On The Heels Of The Mad Cow Pathogen - First Synthetic Anchored Prion

Main Category: CJD / vCJD / Mad Cow Disease
Also Included In: Biology / Biochemistry
Article Date: 21 Oct 2008 - 2:00 PDT

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In the mid-90s, mad cow disease was on everyone's lips and the front page of every newspaper. What made the epizootic outbreak so alarming was the as-sumption that a mutation of the fatal Creutzfeld Jakob Disease (vCJD) could be triggered in humans through the consumption of BSE-infected beef. In both species, the diseases result in brain degeneration. For quite some time, re-search has proceeded on the assumption that wrongly folded prions are re-sponsible. Even if things have quieted down as regards BSE and CJD, the prion-induced diseases remain incurable to this day.

Normal and abnormal prions

Normal prions are relatively simply constructed proteins that occur naturally in brain tissue. New research results even suggest that prions might play a crucial role in the development of new nerve cells in the brain. This means that in most cases prions have a harmless structure. It is still unclear, however, as to why these proteins suddenly alter their structure and make the carrier organism, be it cow, sheep or human, sick.

Researchers suspect a family of the prions, the glycosylphosphatidylinositols, or GPIs. GPIs are made up of sugar and fat residues and anchor prions to the cell surface. This GPI anchoring is conceivably responsible for a prion changing its structure and even prompting other prions to also fold differently. The result is many abnormal prions that clump together, thus damaging the brain.

First synthetic molecule complex

Until recently, attempts to completely isolate these complicated, anchored prions from natural systems had been unsuccessful. The research therefore had to content itself with examining the unusual pathogens without anchors in order to understand their structure, function, stability and folding better. The problem is that simple prions do not cause illness without anchoring. Consequently, it is essential for prion research that prions can be analyzed with GPI anchors. A German-Swiss research team headed by Peter Seeberger, ETH Zurich Pro-fessor of Organic Chemistry, and Christian Becker, Professor from the Labora-tory of Protein Chemistry at the Technical University of Munich, however, can now provide a solution. They have succeeded in synthesizing the first elaborate-ly constructed molecule complex in the lab. Seeberger's group synthesized the GPI anchor, Becker's team the prion. The two substances were then added to-gether to make a whole. "The synthesis of the GPI anchor is an important miles-tone for chemistry because it opens up a whole new range of possibilities and insights for research", stresses Seeberger.

Synthetic prions as tools

Initial tests reveal that the researchers have created the "right" molecule, as the synthetic prion and its GPI can anchor themselves in cell membranes. With the aid of the synthetic molecule complex, prion researchers can investigate the role of the GPI anchor more precisely. Maybe this will eventually help clarify whether the GPI actually influences the folding of the prion or plays a part in other prions suddenly influencing each other negatively. "This is up to the prion researchers under Prof. Adriano Aguzzi at University Hospital Zurich, to whom we can now offer the appropriate tool through our molecules", explains ETH Professor Peter Seeberger.

References

Becker CFW, Liu X, Olschewski D, Castelli R, Seidel R, Seeberger PH: Semisynthesis of a Glycosylphospha-tidylinositol-Anchored Prion Protein, Angewandte Chemie, Volume 47, Issue 43, Pages 8215-8219; doi:10.1002/anie.200802161

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