Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Forgotten and lost - when proteins "shut down" our brain

19.02.2009
Max Planck scientists obtained important new insights into the structure and interaction of a protein relevant to Alzheimer’s disease

Which modules of the tau protein, in neurons of Alzheimer disease patients, may act in a destructive manner were investigated by researchers from the Max Planck Institute for Biophysical Chemistry (Göttingen) and the Max Planck Unit for Structural Molecular Biology (Hamburg) with the help of Nuclear Magnetic Resonance Spectroscopy (PLoS Biology, February 17, 2009).


Schematic view of the tau protein structure.
Image: Max Planck Institute for Biophysical Chemistry / Zweckstetter

Coordination becomes difficult, items disappear, keeping new information in the mind is impossible. Worldwide almost 30 million people suffer from Alzheimer’s disease, a neurodegenerative, irreversible ailment which starts with memory gaps and ends in helplessness and the loss of personality. The most critical factor in developing Alzheimer’s disease is age. Most cases occur after the age of 65.

Two hallmarks are typical for Alzheimer affected brains. One of them, located between nerve cells, is amyloid plaques - extracellular protein aggregates mainly composed of a protein named beta-amyloid. The other clue is intracellular tau fibrils. In the interplay with genetic factors, the latter contribute to a disordered communication within the cell. This triggers cell death.

But the tau protein is not only harmful. Quite the contrary is the case. In its normal non-pathogenic form tau binds to microtubules, long tubular cytoskeletal building blocks, which serve as "tracks" for intracellular transport. In patients afflicted by Alzheimer’s disease or similar dementia, tau is abnormally altered. In its pathogenic form tau possesses more phosphorylated amino acids than in its normal healthy counterpart. "Our interest was focussed on how certain phosphorylated residues alter the structure of tau in a way that it can not bind to microtubules anymore" explains Markus Zweckstetter at the Max Planck Institute for Biophysical Chemistry.

Exotic among proteins

Tau is special and with most biophysical methods, such as X-ray crystallography, not analyzable. Neither heat nor acid can harm the protein. Whereas most proteins fold to adopt the structure necessary for their function, tau can do it in the absence of folded structure, is very flexible and changes its form very rapidly.

With Nuclear Magnetic Resonance Spectroscopy the scientists where able to shed light on the structural properties of tau and followed its fast motions. For the first time detailed investigations of structural changes from a large almost unfolded protein where conducted. "The financial support was granted by the DFG Research Center "Molecular Physiology of the Brain" (CMPB) in Göttingen, the Volkswagen foundation and an institute overlapping Max Planck Society project, ‘Toxic protein conformation’ ", says Christian Griesinger, head of the department of NMR-based structural biology at the Max Planck Institute.

"We can directly observe which modules of the tau protein bind to microtubules. If the protein is equipped with more phosphates than usual we can see that in this case the binding becomes significantly weaker. Tau and microtubule proteins can no longer interact" summarizes Zweckstetter. As a direct consequence the transport along the microtubule "tracks" is disturbed and nerve cell endings do not grow.

The interplay with binding partners is also possibly broken down. "We now hold the tau protein in our hands and are able to look at the interaction with its binding partners in the cell in a very detailed way".

Tau as a drug target

Eckhard and Eva Mandelkow at the Max Planck Unit of Structural Molecular Biology in Hamburg are optimistic about using tau as a pharmaceutical target. On genetically altered mice, Eva Mandelkow and co-workers were able to show reversibility of the fatal consequences of tau aggregation. The next step for the Max Planck scientists would be the investigation of possible inhibitors which interact with the tau protein to prevent fibril formation.

Original work:

Marco D. Mukrasch, Stefan Bibow, Jegannath Korukottu, Sadasivam Jeganathan, Jacek Biernat, Christian Griesinger, Eckhard Mandelkow, Markus Zweckstetter
Structural Polymorphism of 441-residue tau at single residue resolution.
PLoS Biology, February 17, 2009.

Dr. Christina Beck | Max Planck Society
Further information:
http://www.mpg.de/english/

More articles from Life Sciences:

nachricht Novel 'repair system' discovered in algae may yield new tools for biotechnology
29.07.2016 | Boyce Thompson Institute

nachricht Molecular troublemakers instead of antibiotics?
29.07.2016 | Christian-Albrechts-Universität zu Kiel

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Self-assembling nano inks form conductive and transparent grids during imprint

Transparent electronics devices are present in today’s thin film displays, solar cells, and touchscreens. The future will bring flexible versions of such devices. Their production requires printable materials that are transparent and remain highly conductive even when deformed. Researchers at INM – Leibniz Institute for New Materials have combined a new self-assembling nano ink with an imprint process to create flexible conductive grids with a resolution below one micrometer.

To print the grids, an ink of gold nanowires is applied to a substrate. A structured stamp is pressed on the substrate and forces the ink into a pattern. “The...

Im Focus: The Glowing Brain

A new Fraunhofer MEVIS method conveys medical interrelationships quickly and intuitively with innovative visualization technology

On the monitor, a brain spins slowly and can be examined from every angle. Suddenly, some sections start glowing, first on the side and then the entire back of...

Im Focus: Newly discovered material property may lead to high temp superconductivity

Researchers at the U.S. Department of Energy's (DOE) Ames Laboratory have discovered an unusual property of purple bronze that may point to new ways to achieve high temperature superconductivity.

While studying purple bronze, a molybdenum oxide, researchers discovered an unconventional charge density wave on its surface.

Im Focus: Mapping electromagnetic waveforms

Munich Physicists have developed a novel electron microscope that can visualize electromagnetic fields oscillating at frequencies of billions of cycles per second.

Temporally varying electromagnetic fields are the driving force behind the whole of electronics. Their polarities can change at mind-bogglingly fast rates, and...

Im Focus: Continental tug-of-war - until the rope snaps

Breakup of continents with two speed: Continents initially stretch very slowly along the future splitting zone, but then move apart very quickly before the onset of rupture. The final speed can be up to 20 times faster than in the first, slow extension phase.phases

Present-day continents were shaped hundreds of millions of years ago as the supercontinent Pangaea broke apart. Derived from Pangaea’s main fragments Gondwana...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Clash of Realities 2016: 7th Conference on the Art, Technology and Theory of Digital Games

29.07.2016 | Event News

GROWING IN CITIES - Interdisciplinary Perspectives on Urban Gardening

15.07.2016 | Event News

SIGGRAPH2016 Computer Graphics Interactive Techniques, 24-28 July, Anaheim, California

15.07.2016 | Event News

 
Latest News

Vortex laser offers hope for Moore's Law

29.07.2016 | Power and Electrical Engineering

Novel 'repair system' discovered in algae may yield new tools for biotechnology

29.07.2016 | Life Sciences

Clash of Realities 2016: 7th Conference on the Art, Technology and Theory of Digital Games

29.07.2016 | Event News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>