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David Bradley ISSUE #75
October 2008
 
Chasing Down Mad Cows

Researchers in Europe have tracked down the molecular anchor that hooks errant and infectious prions leading to the spongiform encephalopathies—BSE (known colloquially as mad cow disease), scrapie in sheep, and Creutzfeldt-Jakob disease in humans.

Christian Becker, of the Max Planck Institute for Molecular Physiology, in Dortmund, and TU, Munich, Germany; and Peter Seeberger at the ETH, Zurich, Switzerland, and their colleagues, explain that the cause of these lethal brain diseases is a type of protein known as a prion. Prions can convert other healthy proteins in the brain into copies of themselves, causing the characteristic rapidly progressive dementia, memory loss, seizures, personality changes, and hallucinations, as well as speech impairment, jerky movements balance, and coordination problems and changes in gait and posture.

 

Tethering a prion in the lab (Credit: Becker et al/Wiley/VCH)Prions are known to attach to cell membranes through a molecular anchor comprising sugar and lipid components; a so-called glycosylphosphatidylinositol, GPI anchor. This anchoring process strongly influences the transformation of health protein into the pathogenic, prion, form. Becker and Seeberger have now recreated the first GPI-anchored prion in the laboratory, which they say represents a new general method for the synthesis of anchored proteins.

The same technique will not only provide insights into the spongiform encephalopathies, but could have wider application in other diseases in which protein anchors are involved, as well as providing a method to fix proteins for other studies.

Prions are the culprit behind BSE (Photo by David Bradley)The sugar component of natural prion GPI anchors consists of five sugar building blocks, to which additional sugars are attached through branches. Until now, researchers have not had a detailed view of the lipid, or fatty, component of the GPI anchor. The researchers have now synthesized a laboratory version of GPI based on the five sugars and one lipid chain containing 18 carbon atoms.

The centerpiece of their approach was the chemical link between the anchor and the protein. This allowed them to firmly attach the prion to a membrane acting as an artificial cell. This new concept will allow production of sufficient quantities of proteins modified with GPI anchors for in-depth studies. Experiments with the artificial GPI prion protein should help to clarify how the cell membrane of neurons influences the conversion of healthy protein into the pathogenic prion form. This, the researchers say, should finally make it possible to track down the infectious form of the prion.

Angew Chem Int Edn, 47:8215–8219, 2008
TU München: AG Proteinchemie, Prof. Dr. Becker
Seeberger Research Group