08:12am Friday 22 September 2017

Alzheimer’s disease: new insights into Tau protein deposits

The molecular accumulation mechanisms that play a role here may soon be unveiled by an international team of scientists led by the Helmholtz Zentrum München and the Technische Universität München (TUM). This would open the door for new approaches for the treatment of Alzheimer’s disease, as the scientists report in the scientific journal “Cell”.
Alzheimer’s disease: new insights into Tau protein depositsProteins like the so-called heat shock protein Hsp90 play an important role in almost all processes within human cells. They help other proteins fold into their three-dimensional structure or return damaged proteins back into their proper shape.
 

NMR/SAXS structure model of Hsp90-Tau protein complex (light blue – Hsp90, orange – Tau), Source: T. Madl/TUM/HMGU

Recently, there has been increasing evidence indicating that the heat shock protein HSP90 may also be involved in the folding processes of the tau protein. Deposits of tau proteins in brain cells are typical for Alzheimer’s disease and are held responsible for decaying nerve cells.

Hsp90 and Tau: how are they linked?

The protein complex consisting of Hsp90 and Tau is very dynamic. How Hsp90 and tau protein interact and how Hsp90 influences the aggregation of tau proteins with one another has now been resolved by an international team headed by Dr. Tobias Madl, leader of the Emmy-Noether Group Structural Biology of Signal Transduction at the Institute of Structural Biology at the Helmholtz Zentrum München and leader of the BioSysNet Working Group and TUM Junior Fellow at the Technische Universität München as well as Prof. Stefan Rüdiger from the Dutch University of Utrecht.

For their studies they used a combination of very different techniques like magnetic resonance spectroscopy, small-angle X-ray scattering and computer modeling, to determine structure and dynamics of the interactions between the two biomolecules. While dissolved tau proteins look more like long, stretched chains, HSP90 binds predominantly proteins that have already been prefolded. This contradiction has now been resolved: For Hsp90 the tau protein looks like a prefolded larger protein.

Influencing structural formation 

“Deposits of tau proteins are associated with Alzheimer’s disease. We have discovered the protein regions in which the proteins interact. This is a novel and important starting point for influencing structural formation and for developing future therapies for Alzheimer’s disease,” says Madl.

In addition to Alzheimer’s disease, further neurodegenerative diseases are caused by protein aggregation. Folding proteins also play a role in the development of cancer and cystic fibrosis. These scientific insights thus provide an important basis for better understanding the disease mechanisms.

The research was funded by the European Community, the German Research Foundation (DFG), the Dutch Organization for Scientific Research (NWO), the Austrian Academy of Sciences, the Portugese Fundação para a Ciência e a Tecnologia and the National Institutes of Health (USA), as well as the Bavarian Ministry of Science and Research. The small-angle X-ray scattering (SAXS) experiments were conducted in the outstation of the EMBL at DESY in Hamburg. The computer modeling was done at the Leibniz Supercomputing Center of the Bavarian Academy of Sciences.

Further Information

Original publication: 
Karagoz, G. E. et al. (2014), Hsp90-Tau Complex Reveals Molecular Basis for Specificity in Chaperone Action. Cell, doi: 10.1016/j.cell.2014.01.037

Link to publication

Helmholtz Zentrum München, as German Research Center for Environmental Health, pursues the goal of developing personalized medical approaches for the diagnosis, treatment and prevention of major widespread diseases such as diabetes mellitus and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The head office of the Center is located in Neuherberg in the north of Munich. Helmholtz Zentrum München has a staff of about 2,200 people and is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 34,000 staff members. 

Technische Universität München (TUM) is one of Europe’s leading research universities, with around 500 professors, 10,000 academic and non-academic staff, and 36,000 students. Its focus areas are the engineering sciences, natural sciences, life sciences and medicine, reinforced by schools of management and education. TUM acts as an entrepreneurial university that promotes talents and creates value for society. In that it profits from having strong partners in science and industry. It is represented worldwide with a campus in Singapore as well as offices in Beijing, Brussels, Cairo, Mumbai, and São Paulo. Nobel Prize winners and inventors such as Rudolf Diesel and Carl von Linde have done research at TUM. In 2006 and 2012 it won recognition as a German “Excellence University.” In international rankings, it regularly places among the best universities in Germany. 

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Scientific contact
Dr. Tobias Madl, Helmholtz Zentrum München – Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Institute of Structural Biology, Ingolstaedter Landstr. 1, D-85764 Neuherberg – Tel. +49 89 289-13018 – E-mail


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