Scientists are finding a way to detect spectral signals from amyloid fibrils


Data obtained from the Resource Center “The Center for Molecular and Cell Technologies” of the University of St. Petersburg Research Park. Credit: SPbU

Alzheimer’s disease is the most common neurodegenerative disorder in which neurons are gradually extinguished, causing dementia. The exact mechanism and causes of this disorder have not yet been identified. However, amyloid plaques are known to form in the brains of patients. Plates consist of amyloid fibrils, which are special filamentous assemblages formed by amyloid proteins.

“The number of patients with neurodegenerative disorders will continue to grow in the future. Thanks to humanity’s success in treating cancer and cardiovascular disease, more and more people are living to the age of 80. At this age, the risk of developing neurodegenerative disorders, including Alzheimer’s disease, are very high. Unfortunately, no remedies for these diseases have yet been found, “says Nikolai Skrynnikov, co-author of the research, Ph.D., professor, head of the biomolecular NMR laboratory of St. Petersburg University.

According to Nikolai Skrynnikov, scientists have relatively recently deciphered the structural features of amyloid deposits. However, a more detailed study of amyloidogenesis faces several difficulties. In particular, this is due to brain tissue coexist with other structural forms of amyloidogenic protein. These are monomers, proteolytic fragments and various oligomers, some of which serve as “seeds” for the creation of new fibrils. Analyzing this mix is ​​an important challenge. For example, when studying amyloidogenic samples by nuclear magnetic resonance (NMR) spectroscopy, a multitude of signals are obtained that originate not only from fibrils that are of interest to scientists, but also from other species. of proteins. Therefore, experts are looking for ways to separate spectral signals from fibrils and other concomitant structural forms.

The most obvious and simplest method to achieve this goal is the so-called ‘diffusion filter.’ This is a special NMR experiment that separates signals from heavy fibrils and other more mobile components in the sample. however, about ten years ago a few days ago, scientists at Oxford University published two articles questioning the viability of this filter for samples of amyloid fibrils and then research in this field was he stopped.

Scientists are finding a way to detect spectral signals from amyloid fibrils

Data obtained from the Resource Center “Magnetic Resonance Imaging Research Center” of the University of St. Petersburg Research Park. Credit: SPbU

“The movement of a it can be compared to the random movement of a trunk on the surface of a lake, while the movement of a monomer is like that of a pine needle. Oxford researchers argued that record rotation could be faster; as it rotates, the linear velocity at the ends of the register proves to be high enough. For this reason, according to the authors, it becomes impossible to distinguish between a rapidly rotating trunk and an agile needle, “explains Nikolai Skrynnikov.” But that is far from the truth. “

Scientists at the University of St. Petersburg tested the assertion of their Oxford colleagues and not only refuted it, but also created a new theory of the diffusion NMR experiment. In addition, the researchers described the essence of the effect using three methods: the analytical method, that is, deriving a compact formula that reflects the result of the experiment; the numerical method, that is, solving some differential equation using a suitable numerical algorithm; and the Monte Carlo method, i.e., by computer simulation to capture random movements of fibril in solution. All three methods showed virtually identical results, thus validating the new theory.

For the experimental verification of the new theory, researchers have resorted to the yeast protein Sup35, which is known to have amyloidogenic properties. Scientists at the University of St. Petersburg played a prominent role in early studies on this protein. Professor Sergey Inge-Vechtomov, his students and followers were among the first Sup35 researchers. The research team of the Biomolecular NMR Laboratory of the University of St. Petersburg, together with scientists from the University’s Department of Genetics and Biotechnology, used Sup35 as a model system to demonstrate that the use of a diffusion in samples containing amyloid fibrils is really possible. The researchers successfully obtained a spectrum of fibrils, “cleaned” of other spectral signals.

“Twenty to thirty years ago, scientists had little understanding of what happens to the human brain with the onset of dementia. Gradually, knowledge has been accumulating and new research methods have been developed. Thank you to these methods, we now know of the existence of have amyloid deposits and have a fairly detailed idea of ​​their structure, “notes Nikolai Skrynnikov. “Our theory and test are a contribution to the fundamental knowledge on which medical pharmacists rely to search for new drugs. In the future, our proposed diffusion filter for NMR experiments in amyloidogenic systems may aid in this search.” .

Understand the growth of disease-causing protein fibers

More information:
Boris B. Kharkov et al, Role of rotational motion in diffusion NMR experiments in supramolecular assemblies: application to Sup35NM fibrils, Angewandte Chemie International Edition (2021). DOI: 10.1002 / anie.202102408

Citation: Scientists find a way to detect spectral signals of amyloid fibrils (2021, May 26) recovered on May 26, 2021 at fibrils.html

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