Anchoring Mad Cows

Author:  Dunia Rassy
Institution:  London School of Hygiene and Tropical Medicine
Date:  October 2008

A major step towards resolving the mechanism by which prions become disease agents has been achieved as a result of the teams headed by Christian F. Becker at the TU Munich and Peter H. Seeberger at the ETH Zurich. Together, they created the first synthetic form of a prion, the protein responsible of diseases such as mad cow in animals or Creutzfeld-Jakob disease in humans. This synthetic protein also happens to be the first including a GPI anchor which helps them attach to cell membranes. The findings were published on the latest issue of the German journal Angewandte Chemie.

Former studies had already demonstrated that the GPI anchor is essential to prions if they are meant to be infectious. However, until this breakthrough, nobody knew how to create an artificial GPI anchor and attach it to proteins. The glycosylphospatidylinositol (GPI) anchor is made up by a string of sugars and fats and may be added up to proteins' tails shortly after being produced. Becker then inferred that he would have to attach sugars to the protein, one by one, and protect them from unwanted chemical reactions with carbon molecules which were later removed. The resulting anchor was coated with the amino acid cysteine and connected to a prion containing an extra sulfur-rich group named thioester. Cysteine and thioester react and firmly join the anchor and the prion, allowing the latter to attach to membranes.

Scientists believe that this anchoring of prions is related to their transformation into malignant forms that damage brain tissue. Once the prion has undergone the transformation, it can convert normal prions into the pathogenic forms and clump together into disease-causing plaques. Future experiments with the synthetic GPI prion will help clarify first, if they are the real cause of mad cow disease and similar disorders, and second, if the attachment of the prion to the membrane has to do with the transformation. In addition, the achievement will probably allow researchers to track down infectious prions.

Potential applications of the synthetic GPI anchor go further than prion diseases. Humans have around 45 proteins with an anchor and they participate in the recognition, transportation, and binding of other proteins. The GPI anchor acts as a powerful signal for the trafficking of proteins and may activate the immune system. The lack of GPI addition results in paroxysomal nocturnal hemoglobinuria, a rare, but life-threatening disorder. Likewise, defects in genes codifying the GPI anchor may lead to metabolic or genetic syndromes such as Marfan's. The fact that this novel technique provides a method of obtaining large numbers of proteins, with intact GPI anchors, will probably boost research in these areas.

Written by: Dunia Rassy

Edited by: Jeff Kost

Published by: Hoi See Tsao