Please activate JavaScript!
Please install Adobe Flash Player, click here for download
ePaper created 2012-09-28, 09:46:25 | version 1.24.0
2|2012 Research in Jülich 19 with others. As soon as this fatal proce- dure has started, more and more protein molecules attach themselves to the ag- gregate, which is at first tiny but then begins to form long threads – the dread- ed amyloid fibrils. Unless they are bro- ken down by the cell’s “clean-up squads”, they accumulate and ultimately destroy the cell. Its place in the brain is filled by the clumped fibrils, which are visible under the microscope as amyloid plaques in Alzheimer’s, Parkinson’s, and Creutzfeldt-Jakob disease. Philipp Neudecker from the Institute of Complex Systems (ICS) analysed the intermediate stage of protein folding, which stands at the crossroads between the working protein and the dangerous fibrils. “This state is necessary for the protein to fold up properly within less than a second,” he explains. “However, this process is something of a balancing act, because it may also cause fibrils to be formed.” It only exists for an ex- tremely short period of time, no more than a few thousandths of a second. His team succeeded in observing these “borderline cases” closely during this fleeting moment and in analysing the process of folding in great detail using nuclear magnetic resonance spectros- copy. The method, NMR for short, shows the exact spatial structure of the short- lived unstable intermediate stage in atomic resolution. ERRORS INCREASE WITH AGE In his experiments carried out mostly at the University of Toronto, Neudecker found out that the arrangement of the last four amino acids in the molecule consisting of a total of 59 components plays a decisive role. This end of the chain normally forms a string that is aligned almost in parallel with the first building blocks of the molecule. This ar- rangement prevents further proteins from attaching themselves to the mole- cule. In the intermediate state, it is pre- cisely this last protective section of the molecule that is not yet folded. The be- ginning of the protein is open to further protein molecules, enabling fibrils to form spontaneously. It is not always clear why the balanc- ing act ends in disaster in individual cases. “The formation of the initial aggre- gates – a process referred to as nuclea- tion – is a relatively rare event,” reports Neudecker. “Of course, it only occurs when several such molecules meet, and is therefore extremely dependent on the concentration of the protein variant that tends to aggregate.” With increasing age, however, misfolded proteins are in- creasingly likely to accumulate. It is also assumed that the repair mechanisms able to either whip the protein molecules into shape or eliminate them become less effective with age. “Environmental impacts, such as natural or artificial chemicals, are also suspected of playing a role in the formation of amyloid fibrils, as are genetic defects,” explains Neu- decker. HOPE FOR TREATMENT “Our research is of a very basic na- ture,” says the researcher, who came to Jülich from Toronto last spring. He never- theless expects the results to provide great benefits, for example for the diag- nosis and treatment of Alzheimer’s. “There is an almost alarming lack of knowledge on the fundamental mecha- nisms in the decisive initial stages of the disease – which constitutes a great bar- rier to the development of new drugs.” It was recently reported at a specialist conference in Paris that none of the 200 potential active ingredients for Alzhei- mer’s that have undergone clinical trials so far is actually used as a drug today. “By analysing the mechanisms that mark the beginning of such diseases, we can contribute to progress in this area,” says Neudecker. :: RESEARCH AT THE CENTRE | Proteins Source P. Neudecker, P. Robustelli, A. Cavalli, P. Walsh, P. Lundström, A. Zarrine-Afsar, S. Sharpe, M. Vendruscolo & L. E. Kay: Structure of an Interme- diate State in Protein Folding and Aggregation, Science, Vol. 336, p. 362, 2012. This image shows the correctly folded molecule. This intermediate stage occurs during the folding process of a protein molecule that tends to clump under unfavourable conditions.