When polypeptides fail to achieve or maintain their proper conformation, they commonly aggregate into abnormal “amyloid fibril” structures. Amyloid fibrils define a diverse group of degenerative conditions, including amyotrophic lateral sclerosis, prion diseases, and Alzheimer and Parkinson diseases.
In Alzheimer disease, the amyloid fibrils are deposited extracellularly; however, in Parkinson and Huntington disease, similar amyloid fibrils accumulate in the cytoplasm and nucleus of the cell respectively. How amyloid formation promotes disease has generated considerable debate, though mounting evidence implicates the early protofibrillar aggregates as the toxic species.
In a new study in the open-access journal PLoS Biology, Leila Luheshi et al. worked with the fruit fly Drosophila to identify the intrinsic determinants of amyloid ß (Aß) pathogenicity in an animal model of Alzheimer disease. (Aß peptide is a primary component of amyloid plaques in the brains of patients with Alzheimer disease.) Determining how amyloid formation causes disease requires a better understanding of the molecular and biophysical conditions that promote protein aggregation. But such an understanding has proven technically challenging, in part because protein misfolding and aggregation in test tubes can’t replicate cellular pathways designed to mitigate the toxic effects of these events. Luheshi et al. circumvented this problem by integrating computational predictions of protein aggregation propensities with in vitro experiments to test the predictions and in vivo mutagenesis experiments to link predicted aggregation propensity with observed neurodegeneration in the flies.
Overall, the researchers found a clear correlation between a variant’s predicted tendency to aggregate and its influence on fly longevity. The same relationship was seen between predicted aggregation propensity and locomotion, though a few variants did not follow this pattern. An interesting case presented with a variant (131E/E22G), whose neuronal effects did not match its predicted aggregation propensity. The 131E/E22G peptide aggregated at rates similar to the Alzheimer variant in vitro as well as in the fly brains. But because the 131E/E22G peptide deposits were not accompanied by cavities in brain tissue—a telltale sign of neurodegeneration—the flies showed no neurological deficits.
This finding fits with reports that the density of Aß plaques in elderly patients with Alzheimer disease does not correlate with the severity of clinical symptoms. Instead, it is the soluble protofibrillar aggregates, not the mature amyloid plaques, that cause neurodegeneration. Recomputing the propensities of each Aß variant to form these protofibrillar species revealed not only an improved overall correlation with toxicity, but it also brought the previously anomalous 131E/E22G variant in line with the prediction algorithm.
Altogether, these results show that Aß’s toxic effects in a living organism can be predicted based on a computational analysis of its tendency to form protofibrillar aggregates. And even though cells have evolved multiple mechanisms to regulate folding, the researchers argue, it is the intrinsic tendency of the peptide’s sequence to aggregate that governs its pathological propensity. Though the researchers focused on the peptide most closely associated with Alzheimer disease, they believe their approach will work for many other diseases as well.
Andrew Hyde | alfa
How brains surrender to sleep
23.06.2017 | IMP - Forschungsinstitut für Molekulare Pathologie GmbH
A new technique isolates neuronal activity during memory consolidation
22.06.2017 | Spanish National Research Council (CSIC)
An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.
Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...
Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.
Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...
Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.
As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...
Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.
With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...
Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine
Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...
19.06.2017 | Event News
13.06.2017 | Event News
13.06.2017 | Event News
23.06.2017 | Physics and Astronomy
23.06.2017 | Physics and Astronomy
23.06.2017 | Information Technology