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Forschungszentrum Jülich - Annual Report 2012

Creatingknowledge Annual Report 2012 | Forschungszentrum Jülich 31 cells. He was particularly interested in a short-lived intermediate stage that occurs during the folding process be- fore the protein is eventually complete. This process is a delicate balancing act. The intermediate stage can either result in the functional molecule, or it can produce a faulty version that tends to bond with others. As soon as this fatal procedure has started, more and more protein molecules attach them- selves to the initially tiny aggregate – the dreaded amyloid fibrils are formed. Unless they are removed by the cell’s ‘rubbish collection’, these fibrils cause it to die. In their place, the brain then contains the protein lumps that Alois Alzheimer saw under the microscope. Neudecker therefore took a closer look at the intermediate stage that This image shows the correctly folded molecule. hangs in the balance between the cor- rectly functioning protein and the dan- gerous fibrils. For this purpose, he used a method of nuclear magnetic reso- nance spectroscopy, or NMR for short, that was refined specifically for short- lived molecule states. It shows the exact three-dimensional shape of the volatile structure that exists only for a few thousandths of a second. And Neudecker’s team were successful in observing the molecule in detail during this decisive moment. “This state is necessary for the protein to fold proper- ly within less than a second,” he ex- plains. “However, when things go wrong, this stage can also cause fibrils to be formed.” In his experiments, performed mostly at the University of Toronto, Neudecker discovered that the fate of the ‘border- line cases’ is decided by the arrange- ment of only four amino acids in the molecule consisting of a total of 59 components. They form the end of the protein string and are usually aligned almost in parallel with the first amino acids of the molecule. In this way, no other proteins can bind to the molecule. In the intermediate state, it is pre- cisely this last protective section of the molecule that is not yet folded. The beginning of the protein thread is open and unprotected, so that other protein molecules can attach themselves to it. This can be the beginning of a fatal chain reaction where small fibrils initial- ly form, then larger ones, and finally plaques. Risk increases with age The researchers are still unsure as to why the balancing act sometimes ends in disaster. “The formation of the initial aggregates – a process referred to as nucleation – is luckily a relatively rare event,” reports Neudecker. “It all comes down to how many molecules come together of the protein variant which tends to aggregate.” However, with increasing age, there is an increased probability of such molecules accumu- lating, and repair mechanisms are no longer as effective. “Environmental impacts, such as natural or artificial chemicals, are suspected to be partly responsible for the formation of amyloid fibrils, as are genetic defects,” says Neudecker. He hopes that his findings will con- tribute to enabling an early diagnosis of Alzheimer’s disease and ultimately the development of effective drugs. In September 2012, Philipp Neudecker received the Ulrich Hadding Research Award from the Biological-Medical Research Centre (BMFZ) of Heinrich Heine University Düsseldorf for his work. This intermediate stage occurs during the folding process of a protein molecule that tends to clump under unfavourable conditions.